Submissions for variant NM_000535.7(PMS2):c.1708A>G (p.Asn570Asp)

gnomAD frequency: 0.00048  dbSNP: rs115670442

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129033	SCV000172943	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195850	SCV000253292	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001719888	SCV000279145	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719888	SCV000601827	benign	not provided	2023-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121841	SCV000697309	likely benign	not specified	2019-02-01	criteria provided, single submitter	clinical testing	Variant summary: The variant, PMS2 c.1708A>G (p.Asn570Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 278512 control chromosomes, predominantly at a frequency of 0.0017 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1708A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000129033	SCV000910757	likely benign	Hereditary cancer-predisposing syndrome	2016-02-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164192	SCV001326301	uncertain significance	Lynch syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV000121841	SCV002067280	uncertain significance	not specified	2019-04-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129033	SCV002530221	likely benign	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129033	SCV004014901	benign	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing
ITMI	RCV000121841	SCV000086039	not provided	not specified	2013-09-19	no assertion provided	reference population