Submissions for variant NM_000251.3(MSH2):c.182A>C (p.Gln61Pro)

dbSNP: rs587779113

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703978	SCV000730543	likely benign	not provided	2020-10-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16995940, 17720936, 26333163, 25133505, 18383312, 20176959, 31159747, 32957588)
Counsyl	RCV000662761	SCV000785555	uncertain significance	Lynch syndrome 1	2017-09-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000708715	SCV000822049	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000708715	SCV000908272	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 61 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant protein to be functional in yeast mutator and protein binding assays (PMID: 17720936, 20176959). This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 25133505). This variant has been identified in 1/232376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000708715	SCV001173915	likely benign	Hereditary cancer-predisposing syndrome	2020-03-04	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.
Invitae	RCV001218170	SCV001390042	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662761	SCV004018375	likely benign	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317078	SCV004020513	uncertain significance	not specified	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.182A>C (p.Gln61Pro) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 232376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.182A>C has been reported in the literature in an individual affected with ovarian cancer and colorectal cancer who fulfilled at least one of the revised Bethesda guidelines and in affected individuals undergoing genetic testing for hereditary cancers (e.g. Tsaousis_2019, Germani_2020, Pemov_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Functional studies examining the variant in a yeast model system and using a DNA mismatch repair proficiency screen showed no damaging effect of this variant (Gammie_2007, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 17720936, 32957588, 33357406, 25133505, 34964002, 31159747). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997154	SCV004831983	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 61 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant protein to be functional in yeast mutator and protein binding assays (PMID: 17720936, 20176959). This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 25133505). This variant has been identified in 1/232376 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.