Submissions for variant NM_000179.3(MSH6):c.102C>A (p.Ala34=)

gnomAD frequency: 0.00013  dbSNP: rs201132087

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162474	SCV000212845	likely benign	Hereditary cancer-predisposing syndrome	2015-11-22	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	RCV001084817	SCV000260625	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162474	SCV000685155	likely benign	Hereditary cancer-predisposing syndrome	2016-04-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759840	SCV000889450	benign	not provided	2022-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194333	SCV001363793	benign	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.102C>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00019 in 235824 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.102C>A in individuals affected with Hereditary Non-Polyposis Colon Cancer 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 (2xbenign, 2xlikely benign). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000759840	SCV001908522	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162474	SCV002535583	benign	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995198	SCV004827919	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357215	SCV001552608	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ala34= variant was not identified in the literature nor was it identified in the UMD-LSDB. The variant was identified in dbSNP (ID: rs201132087) as "With Likely benign allele", and in ClinVar (classified as benign by Invitae and one clinical laboratory; as likely benign by Ambry Genetics and Color).The variant was identified in control databases in 47 of 263666 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 47 of 18376 chromosomes (freq: 0.003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ala34= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.