ClinGen Sequence Variant Interpretation Recommendation for de novo Cri

ClinGen Sequence Variant Interpretation Recommendation for de novo Cri - Description


-Version 11 Working Group Pagehttps//clinicalgenomeorg/working-groups/sequence-variant-interpretation/Date Approved March 18 2018Changes from v1 Clarified that confirmed/assumed is with regards to par Download

Tags

variant novo points parental novo variant parental points relationships ps2 phenotype level criteria strength point confirmed gene consistent awarded

Embed / Share - ClinGen Sequence Variant Interpretation Recommendation for de novo Cri


Presentation on theme: "ClinGen Sequence Variant Interpretation Recommendation for de novo Cri"— Presentation transcript


1 ClinGen Sequence Variant Interpretation
ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 201 8 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo statu s SVI Recommendation for De Novo Criteria (PS2 & PM6) - Version 1. 1 The Sequence Variant Interpretation (SVI) Working Group proposes a point - based system to determine the strength of de novo evidence (ACMG/AMP criteria codes PS2 and PM6) based upon three parameters: ● confirmed parental relationships versus assumed parental relationships status ● phenotypic consistency ● number of de novo observations To determine the appropriate strength level to apply for de novo occurrence(s), each proband with a de novo variant is awarded a point value based upon phenotypic consistency and co nfirmed or assumed parental relationships (Table 1). The combined point value of all de novo occurrences is then compared to Table 2 to determine the applicable evidence strength level. For example, if a NIPBL variant was de novo in one patient with Cornel ia de Lange syndrome , with confi r med parental relationships (2 points; Table 1) and de novo in two additional unrelated patients with Cornelia de Lange syndrome with unconfirmed parental relationships (1 + 1 points; Table 1), then VeryStrong evidence level is applied (PS2_VeryStrong) based on combined point value of 4 (Table 2). If the parents have not been tested for parentage or for the variant, no points should be awarded. Table 1. Points * awarded per de novo occurrence Phenotypic consistency Points per Proband de novo with confirmed parental relationships de novo with unconfirmed parental relationships Phenotype highly specific for gene 2 1 Phenotype consistent with gene but not highly specific 1 0.5 Phenotype consistent with gene but not highly specific and high genetic heterogeneity* * 0.5 0.25 Phenotype not consistent with gene 0 0 *Note that these points are not equivalent to the points used to classify a variant per the Tavtigian et al 2020 “ (itting a naturally scaled point system to the ACM)/AM2 variant classification guidelines” * *Maximum allowable value of 1 may contribute to overall score Table 2. Recommend ation for determining the appropriate ACMG/AMP evidence strength level for de novo occurrence(s) Supporting (PS2_Supporting or PM6_Supporting) Moderate (PS2_Moderate or PM6) Strong (PS2 or PM6_Strong) Very Strong (PS2_VeryStrong or PM6_VeryStrong) 0.5 1 2 4 ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 201 8 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo statu s For all uses of de novo criteria, the phenotype in the patient must be consistent with the gene/disease association as recommended in the ACMG/AMP guidelines. When the patient’s phenotype is consistent with the gene/disease association but not highly specific, we recommend decreasing the points awarded. For example: ● A patient with early infantile epileptic encephalopathy and a de novo SIK1 variant wi th confirmed parental relationships is awarded 1 point (as the patient’s phenotype is consistent with the gene but not highly specific and the variant is de novo with confirmed parental relationships ). If this patient is the only de novo occurrence for the variant, then a Moderate strength level (PS2_Moderate) is applied. ○ If two additional unrelated patients with early infantile epileptic encephalopathy and a de novo SIK1 variant with confirmed parental relationships are identified, then the combined point value is 3 (as each patient is awarded 1 point). For these combined occurrences, a Strong strength level (PS2) is applied as the points reach the Strong threshold (2 points) but not the VeryStrong threshold (4 points). ● A patient with nonsyndromic intellect ual disability and a de novo ASH1L variant is awarded 0.5 points (as the variant is de novo with confirmed parental relationships and patient’s phenotype is consistent with the gene but not highly specific and there is significant evidence of genetic heter ogeneity). If this patient is the only de novo occurrence for the variant, then a Supporting strength level (PS2_Supporting) is applied. ○ If a second patient with nonsyndromic intellectual disability and a de novo ASH1L variant with confirmed parental relat ionships is identified, then the combined point value is 1 (as each patient is awarded 0.5 points). For these combined occurrences, a Moderate strength level (PS2_Moderate) is applied. ● A patient with developmental delay but no other features of Cornelia de Lange syndrome and a de novo NIPBL variant with unconfirmed parental relationships is awarded zero points as this phenotype is not consistent with the gene/disease association. If this patient was the only de novo occurrence for the variant, then no de no vo criteria are applied. Additional considerations for applying de novo criteria based on inheritance: ● Conditions with X - linked inheritance : if the variant occurs de novo in an unaffected carrier mother, and family history is consistent - i.e. , she has no affected brothers/other male relatives apart from her affected son(s) – de novo criteria may be applied despite the fact that she is unaffected. ● Autosomal recessive conditions: for a de novo occurrence in a gene associated with a condition inhe rited in an autosomal recessive pattern without an additional pathogenic/likely pathogenic variant identified, the strength of evidence should be decreased by one level. ● Mosaicism: for cases with apparent germline mosaicism (multiple affected siblings with both parents negative for the variant), parental relationships must be confirmed in order for de novo criteria to apply. ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 2018 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo statu s For all uses of de novo criteria, the phenotype in the patient must be consistent with the gene/disease association as recommended in the ACMG/AMP guidelines. When the patient’s phenotype is consistent with 琀栀攀 最攀渀攀⼀搀椀獥愀獥 愀獳漀挀椀愀琀椀漀渀 戀甀琀 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀Ⰰ 眀攀 爀攀挀漀洀洀攀渀搀 搀攀挀爀攀愀獩渀最 琀栀攀 瀀漀椀渀琀猠愀眀愀爀搀攀搀⸀ 䘀漀爀  攀砀愀洀瀀氀攀㨀 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 攀愀爀氀礀 椀渀昀愀渀琀椀氀攀 攀瀀椀氀攀瀀琀椀挀 攀渀挀攀瀀栀愀氀漀瀀愀琀栀礀 愀渀搀 愀  de novo SIK1 variant wi th confirmed parental relationships is awarded 1 point (as the patient’s phenotype is consistent with the gene but 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀 愀渀搀 琀栀攀 瘀愀爀椀愀渀琀 椀猠 de novo with confirmed parental relationships ). If this patient is the only de novo occurrence for the variant, then a Moderate strength level (PS2_Moderate) is applied. 䤀昀 琀眀漀 愀搀搀椀琀椀漀渀愀氀 甀渀爀攀氀愀琀攀搀 瀀愀琀椀攀渀琀猠眀椀琀栀 攀愀爀氀礀 椀渀昀愀渀琀椀氀攀 攀瀀椀氀攀瀀琀椀挀 攀渀挀攀瀀栀愀氀漀瀀愀琀栀礀 愀渀搀 愀  de novo SIK1 variant with confirmed parental relationships are identified, then the combined point value is 3 (as each patient is awarded 1 point). For these combined occurrences, a Strong strength level (PS2) is applied as the points reach the Strong threshold (2 points) but not the VeryStrong threshold (4 points). 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 渀漀渀獹渀搀爀漀洀椀挀 椀渀琀攀氀氀攀挀琀 甀愀氀 搀椀獡戀椀氀椀琀礀 愀渀搀 愀  de novo ASH1L variant is awarded 0.5 points (as the variant is de novo with confirmed parental relationships and patient’s phenotype is 挀漀渀獩獴攀渀琀 眀椀琀栀 琀栀攀 最攀渀攀 戀甀琀 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀 愀渀搀 琀栀攀爀攀 椀猠獩最渀椀昀椀挀愀渀琀 攀瘀椀搀攀渀挀攀 漀昀 最攀渀攀琀椀挀 栀攀琀攀爀 漀最攀渀攀椀琀礀⤀⸀ 䤀昀 琀栀椀猠瀀愀琀椀攀渀琀 椀猠琀栀攀 漀渀氀礀  de novo occurrence for the variant, then a Supporting strength level (PS2_Supporting) is applied. 䤀昀 愀 獥挀漀渀搀 瀀愀琀椀攀渀琀 眀椀琀栀 渀漀渀獹渀搀爀漀洀椀挀 椀渀琀攀氀氀攀挀琀甀愀氀 搀椀獡戀椀氀椀琀礀 愀渀搀 愀  de novo ASH1L variant with confirmed parental relat ionships is identified, then the combined point value is 1 (as each patient is awarded 0.5 points). For these combined occurrences, a Moderate strength level (PS2_Moderate) is applied. 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 搀攀瘀攀氀漀瀀洀攀渀琀愀氀 搀攀氀愀礀 戀甀琀 渀漀 漀琀栀攀爀 昀攀愀琀甀爀攀猠漀昀 䌀漀爀渀攀氀椀愀 搀攀 䰀愀渀最攀 獹渀搀爀漀洀攀 愀渀搀 愀  de novo NIPBL variant with unconfirmed parental relationships is awarded zero points as this phenotype is not consistent with the gene/disease association. If this patient was the only de novo occurrence for the variant, then no de no vo criteria are applied. Additional considerations for applying de novo criteria based on inheritance: 䌀漀渀搀椀琀椀漀渀猠眀椀琀栀  氀椀渀欀攀搀  椀渀栀攀爀椀琀愀渀挀攀 㨀 椀昀  瘀愀爀椀愀渀琀 漀挀挀甀爀猠 de novo in an unaffected carrier mother, and family history is consistent - i.e. , she has no affected brothers/other male relatives apart from her affected son(s) de novo criteria may be applied despite the fact that she is unaffected. 䄀甀琀漀獯洀愀氀 爀攀挀攀獳椀瘀攀 挀漀渀搀椀琀椀漀渀猺 昀漀爀 愀  de novo occurrence in a gene associated with a condition inhe rited in an autosomal recessive pattern without an additional pathogenic/likely pathogenic variant identified, the strength of evidence should be decreased by one level. 䴀漀獡椀挀椀獭㨀 昀漀爀 挀愀獥猠眀椀琀栀 愀瀀瀀愀爀攀渀琀 最攀爀洀氀椀渀攀 洀漀獡椀挀椀獭 ⠀洀甀氀琀椀瀀氀攀 愀昀昀攀挀琀攀搀 獩戀氀椀渀最猠眀椀琀栀 戀漀琀栀 瀀愀爀攀渀琀猠渀攀最愀琀椀瘀攀 昀漀爀 琀栀攀 瘀愀爀椀愀渀琀⤀Ⰰ  瀀愀

2 攀渀琀愀氀 爀攀氀愀琀椀
攀渀琀愀氀 爀攀氀愀琀椀漀渀獨椀瀀猠 洀甀獴 戀攀 挀漀渀昀椀爀洀攀搀 椀渀 漀爀搀攀爀 昀漀爀  de novo criteria to apply. ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 2018 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo status SVI Recommendation for De Novo Criteria (PS2 & PM6) - Version 1. 1 The Sequence Variant Interpretation (SVI) Working Group proposes a point - based system to determine the strength of de novo evidence (ACMG/AMP criteria codes PS2 and PM6) based upon three parameters: 挀漀渀昀椀爀洀攀搀  瀀愀爀攀渀琀愀氀 爀攀氀愀琀椀漀渀獨椀瀀猠 瘀攀爀獵猠愀獳甀洀攀搀 瀀愀爀攀渀琀愀氀  爀攀氀愀琀椀漀渀獨椀瀀猀 獴愀琀甀猀 瀀栀攀渀漀琀礀瀀椀挀 挀漀渀獩獴攀渀挀礀 渀甀洀戀攀爀 漀昀  de novo observations To determine the appropriate strength level to apply for de novo occurrence(s), each proband with a de novo variant is awarded a point value based upon phenotypic consistency and co nfirmed or assumed parental relationships (Table 1). The combined point value of all de novo occurrences is then compared to Table 2 to determine the applicable evidence strength level. For example, if a NIPBL variant was de novo in one patient with Cornel ia de Lange syndrome , with confi r med parental relationships (2 points; Table 1) and de novo in two additional unrelated patients with Cornelia de Lange syndrome with unconfirmed parental relationships (1 + 1 points; Table 1), then VeryStrong evidence level is applied (PS2_VeryStrong) based on combined point value of 4 (Table 2). If the parents have not been tested for parentage or for the variant, no points should be awarded. Table 1. Points * awarded per de novo occurrence Phenotypic consistency Points per Proband de novo with confirmed parental relationships de novo with unconfirmed parental relationships Phenotype highly specific for gene 2 1 Phenotype consistent with gene but not highly specific 1 0.5 Phenotype consistent with gene but not highly specific and high genetic heterogeneity* * 0.5 0.25 Phenotype not consistent with gene 0 0 *Note that these points are not equivalent to the points used to classify a variant per the Tavtigian et al 2020 (itting a naturally scaled point system to the ACM)/AM2 variant classification guidelines” ⩍愀砀椀洀甀洀 愀氀氀漀眀愀戀氀攀 瘀愀氀甀攀 漀昀 ㄀ 洀愀礀 挀漀渀琀爀椀戀甀琀攀 琀漀 漀瘀攀爀愀氀氀 獣漀爀攀 Table 2. Recommend ation for determining the appropriate ACMG/AMP evidence strength level for de novo occurrence(s) Supporting (PS2_Supporting or PM6_Supporting) Moderate (PS2_Moderate or PM6) Strong (PS2 or PM6_Strong) Very Strong (PS2_VeryStrong or PM6_VeryStrong) 0.5 1 2 4 ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 2018 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo statu s For all uses of de novo criteria, the phenotype in the patient must be consistent with the gene/disease association as recommended in the ACMG/AMP guidelines. When the patient’s phenotype is consistent with 琀栀攀 最攀渀攀⼀搀椀獥愀獥 愀獳漀挀椀愀琀椀漀渀 戀甀琀 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀Ⰰ 眀攀 爀攀挀漀洀洀攀渀搀 搀攀挀爀攀愀獩渀最 琀栀攀 瀀漀椀渀琀猠愀眀愀爀搀攀搀⸀ 䘀漀爀  攀砀愀洀瀀氀攀㨀 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 攀愀爀氀礀 椀渀昀愀渀琀椀氀攀 攀瀀椀氀攀瀀琀椀挀 攀渀挀攀瀀栀愀氀漀瀀愀琀栀礀 愀渀搀 愀  de novo SIK1 variant wi th confirmed parental relationships is awarded 1 point (as the patient’s phenotype is consistent with the gene but 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀 愀渀搀 琀栀攀 瘀愀爀椀愀渀琀 椀猠 de novo with confirmed parental relationships ). If this patient is the only de novo occurrence for the variant, then a Moderate strength level (PS2_Moderate) is applied. 䤀昀 琀眀漀 愀搀搀椀琀椀漀渀愀氀 甀渀爀攀氀愀琀攀搀 瀀愀琀椀攀渀琀猠眀椀琀栀 攀愀爀氀礀 椀渀昀愀渀琀椀氀攀 攀瀀椀氀攀瀀琀椀挀 攀渀挀攀瀀栀愀氀漀瀀愀琀栀礀 愀渀搀 愀  de novo SIK1 variant with confirmed parental relationships are identified, then the combined point value is 3 (as each patient is awarded 1 point). For these combined occurrences, a Strong strength level (PS2) is applied as the points reach the Strong threshold (2 points) but not the VeryStrong threshold (4 points). 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 渀漀渀獹渀搀爀漀洀椀挀 椀渀琀攀氀氀攀挀琀 甀愀氀 搀椀獡戀椀氀椀琀礀 愀渀搀 愀  de novo ASH1L variant is awarded 0.5 points (as the variant is de novo with confirmed parental relationships and patient’s phenotype is 挀漀渀獩獴攀渀琀 眀椀琀栀 琀栀攀 最攀渀攀 戀甀琀 渀漀琀 栀椀最栀氀礀 獰攀挀椀昀椀挀 愀渀搀 琀栀攀爀攀 椀猠獩最渀椀昀椀挀愀渀琀 攀瘀椀搀攀渀挀攀 漀昀 最攀渀攀琀椀挀 栀攀琀攀爀 漀最攀渀攀椀琀礀⤀⸀ 䤀昀 琀栀椀猠瀀愀琀椀攀渀琀 椀猠琀栀攀 漀渀氀礀  de novo occurrence for the variant, then a Supporting strength level (PS2_Supporting) is applied. 䤀昀 愀 獥挀漀渀搀 瀀愀琀椀攀渀琀 眀椀琀栀 渀漀渀獹渀搀爀漀洀椀挀 椀渀琀攀氀氀攀挀琀甀愀氀 搀椀獡戀椀氀椀琀礀 愀渀搀 愀  de novo ASH1L variant with confirmed parental relat ionships is identified, then the combined point value is 1 (as each patient is awarded 0.5 points). For these combined occurrences, a Moderate strength level (PS2_Moderate) is applied. 䄀 瀀愀琀椀攀渀琀 眀椀琀栀 搀攀瘀攀氀漀瀀洀攀渀琀愀氀 搀攀氀愀礀 戀甀琀 渀漀 漀琀栀攀爀 昀攀愀琀甀爀攀猠漀昀 䌀漀爀渀攀氀椀愀 搀攀 䰀愀渀最攀 獹渀搀爀漀洀攀 愀渀搀 愀  de novo NIPBL variant with unconfirmed parental relationships is awarded zero points as this phenotype is not consistent with the gene/disease association. If this patient was the only de novo occurrence for the variant, then no de no vo criteria are applied. Additional considerations for applying de novo criteria based on inheritance: 䌀漀渀搀椀琀椀漀渀猠眀椀琀栀  氀椀渀欀攀搀  椀渀栀攀爀椀琀愀渀挀攀 㨀 椀昀  瘀愀爀椀愀渀琀 漀挀挀甀爀猠 de novo in an unaffected carrier mother, and family history is consistent - i.e. , she has no affected brothers/other male relatives apart from her affected son(s) de novo criteria may be applied despite the fact that she is unaffected. 䄀甀琀漀獯洀愀氀 爀攀挀攀獳椀瘀攀 挀漀渀搀椀琀椀漀渀猺 昀漀爀 愀  de novo occurrence in a gene associated with a condition inhe rited in an autosomal recessive pattern without an additional pathogenic/likely pathogenic variant identified, the strength of evidence should be decreased by one level. 䴀漀獡椀挀椀獭㨀 昀漀爀 挀愀獥猠眀椀琀栀 愀瀀瀀愀爀攀渀琀 最攀爀洀氀椀渀攀 洀漀獡椀挀椀獭 ⠀洀甀氀琀椀瀀氀攀 愀昀昀攀挀琀攀搀 獩戀氀椀渀最猠眀椀琀栀 戀漀琀栀 瀀愀爀攀渀琀猠渀攀最愀琀椀瘀攀 昀漀爀 琀栀攀 瘀愀爀椀愀渀琀⤀Ⰰ  瀀愀爀攀渀琀愀氀 爀攀氀愀琀椀漀渀獨椀瀀猠 洀甀獴 戀攀 挀漀渀昀椀爀洀攀搀 椀渀 漀爀搀攀爀 昀漀爀  de novo criteria to apply. ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1 Working Group Page: https://clinicalgenome.org/workin g - groups/sequence - variant - interpretation/ Date Approved: March 18, 2018 Changes from v1: Clarified that confirmed/assumed is with regards to parental relationships and not de novo status SVI Recommendation for De Novo Criteria (PS2 & PM6) - Version 1. 1 The Sequence Variant Interpretation (SVI) Working Group proposes a point - based system to determine the strength of de novo evidence (ACMG/AMP criteria codes PS2 and PM6) based upon three parameters: 挀漀渀昀椀爀洀攀搀  瀀愀爀攀渀琀愀氀 爀攀氀愀琀椀漀渀獨椀瀀猠 瘀攀爀獵猠愀獳甀洀攀搀 瀀愀爀攀渀琀愀氀  爀攀氀愀琀椀漀渀獨椀瀀猀 獴愀琀甀猀 瀀栀攀渀漀琀礀瀀椀挀 挀漀渀獩獴攀渀挀礀 渀甀洀戀攀爀 漀昀  de novo observations To determine the appropriate strength level to apply for de novo occurrence(s), each proband with a de novo variant is awarded a point value based upon phenotypic consistency and co nfirmed or assumed parental relationships (Table 1). The combined point value of all de novo occurrences is then compared to Table 2 to determine the applicable evidence strength level. For example, if a NIPBL variant was de novo in one patient with Cornel ia de Lange syndrome , with confi r med parental relationships (2 points; Table 1) and de novo in two additional unrelated patients with Cornelia de Lange syndrome with unconfirmed parental relationships (1 + 1 points; Table 1), then VeryStrong evidence level is applied (PS2_VeryStrong) based on combined point value of 4 (Table 2). If the parents have not been tested for parentage or for the variant, no points should be awarded. Table 1. Points * awarded per de novo occurrence Phenotypic consistency Points per Proband de novo with confirmed parental relationships de novo with unconfirmed parental relationships Phenotype highly specific for gene 2 1 Phenotype consistent with gene but not highly specific 1 0.5 Phenotype consistent with gene but not highly specific and high genetic heterogeneity* * 0.5 0.25 Phenotype not consistent with gene 0 0 *Note that these points are not equivalent to the points used to classify a variant per the Tavtigian et al 2020 (itting a naturally scaled point system to the ACM)/AM2 variant classification guidelines” ⩍愀砀椀洀甀洀 愀氀氀漀眀愀戀氀攀 瘀愀氀甀攀 漀昀 ㄀ 洀愀礀 挀漀渀琀爀椀戀甀琀攀 琀漀 漀瘀攀爀愀氀氀 獣漀爀攀 Table 2. Recommend ation for determining the appropriate ACMG/AMP evidence strength level for de novo occurrence(s) Supporting (PS2_Supporting or PM6_Supporting) Moderate (PS2_Moderate or PM6) Strong (PS2 or PM6_Strong) Very Strong (PS2_VeryStrong or PM6_VeryStrong) 0.5 1 2

Shom More....
holly
By: holly
Views: 1
Type: Public

Download Section

Please download the presentation after appearing the download area.


Download - The PPT/PDF document "ClinGen Sequence Variant Interpretation Recommendation for de novo Cri" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.

Try DocSlides online tool for compressing your PDF Files Try Now