Submissions for variant NM_000179.3(MSH6):c.926C>G (p.Ser309Cys)

gnomAD frequency: 0.00006  dbSNP: rs544222338

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656891	SCV000149355	uncertain significance	not provided	2024-02-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 31307542, 21437237, 37013556, 35449176, 36243179)
Ambry Genetics	RCV000115446	SCV000215268	likely benign	Hereditary cancer-predisposing syndrome	2021-04-07	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	RCV001089225	SCV000283860	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212637	SCV000601622	uncertain significance	not specified	2016-12-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115446	SCV000902781	likely benign	Hereditary cancer-predisposing syndrome	2016-11-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212637	SCV001360587	likely benign	not specified	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.926C>G (p.Ser309Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251308 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17 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 South Asian origin. c.926C>G has been reported in the literature in individual(s) affected with advanced cancer (Mandelker_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153368	SCV003843782	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529928	SCV004117970	uncertain significance	MSH6-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	The MSH6 c.926C>G variant is predicted to result in the amino acid substitution p.Ser309Cys. This variant has been reported in at least one individual with advanced cancer (Mandelker et al. 2017. PubMed ID: 28873162) and in a patient with ovarian cancer (Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also reported in two individuals with endometrial cancer; however, immunohistochemistry of the tumor found one individual had normal MSH6 staining while MSH6 was absent in the other (Chao et al. 2019. PubMed ID: 31307542). This variant is reported in 0.24% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026048-C-G) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127607/). At this time, while we suspect this variant could be benign (based on minor allele frequency) the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000656891	SCV004146076	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	MSH6: BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353732	SCV000592578	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ser309Cys variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from individuals with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs544222338) as “with uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics and likely benign by Color and Invitae) and UMD-LSDB (observed 1x). The variant was identified in control databases in 75 of 277,020 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,004 chromosomes (freq: 0.00004), European in 3 of 126,576 chromosomes (freq: 0.00002) and South Asian in 71 of 30,780 chromosomes (freq: 0.002). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Ser309Cys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.