Submissions for variant NM_000179.3(MSH6):c.107C>T (p.Ala36Val)

gnomAD frequency: 0.00004  dbSNP: rs61756469

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128922	SCV000172791	likely benign	Hereditary cancer-predisposing syndrome	2021-02-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000220784	SCV000279090	likely benign	not provided	2021-04-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26530882, 23621914, 29616133, 30132833)
Invitae	RCV000226897	SCV000283699	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000412094	SCV000488415	uncertain significance	Lynch syndrome 5	2016-03-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128922	SCV000685162	likely benign	Hereditary cancer-predisposing syndrome	2020-02-19	criteria provided, single submitter	clinical testing
Mendelics	RCV003323293	SCV000837862	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220784	SCV000889452	likely benign	not provided	2022-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780475	SCV000917752	likely benign	not specified	2018-03-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change located outside of any known functional domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. An algorithm developed specifically to ascertain variants in MSH6 gene suggest that this missense change has no impact on MSH6 function (Terui_2013). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5.35 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.107C>T has been reported in the literature in two family members affected with familial non-medullary thyroid cancer without reported personal or family history of Lynch Syndrome; both individuals also carried in-frame variant in GNAS gene (Lu_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000128922	SCV002535589	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149883	SCV003837838	uncertain significance	Breast and/or ovarian cancer	2021-12-29	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153411	SCV003843464	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128922	SCV004014917	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412094	SCV004019032	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003422021	SCV004117484	uncertain significance	MSH6-related condition	2023-05-18	criteria provided, single submitter	clinical testing	The MSH6 c.107C>T variant is predicted to result in the amino acid substitution p.Ala36Val. This variant has been reported in an individual with non-medullary thyroid cancer (Yu et al. 2015. PubMed ID: 26530882). This variant is reported in 0.084% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48010479-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140779/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000220784	SCV004698919	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH6: BP1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356921	SCV001552213	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Ala36Val variant was identified in the literature however the frequency of this variant in an affected population was not provided (Terui_2013_23621914, Yu_2015_26530882). The variant was also identified in the following databases: dbSNP (ID: rs61756469) as “With Uncertain significance allele”, ClinVar (5x as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Geomics) and Clinvitae (4x as uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database and Insight Hereditary Tumors Database. The variant was identified in control databases in 36 of 263104 chromosomes at a frequency of 0.00014 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 5 of 117454 chromosomes (freq: 0.000043), Ashkenazi Jewish in 1 of 9824 chromosomes (freq: 0.0001), East Asian in 14 of 18328 chromosomes (freq: 0.00076), European Finnish in 8 of 25266 chromosomes (freq: 0.0003), and South Asian in 8 of 30212 chromosomes (freq: 0.00026); while the variant was not observed in the African, “Other” and Latino, populations. The p.Ala36 residue is not conserved in mammals and 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.