Submissions for variant NM_000179.3(MSH6):c.1937A>G (p.Lys646Arg)

gnomAD frequency: 0.00004  dbSNP: rs201096652

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000229693	SCV000283737	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000482874	SCV000565219	likely benign	not provided	2018-10-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914, 26689913, 29338689, 31386297)
Ambry Genetics	RCV000491214	SCV000580205	likely benign	Hereditary cancer-predisposing syndrome	2018-07-10	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.
Color Diagnostics, LLC DBA Color Health	RCV000491214	SCV000685240	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 646 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26689913, 30982232), and in an individual affected with endometrial cancer that did not meet Amsterdam II criteria or revised Bethesda guidelines (PMID: 31307542). This variant has been identified in 9/251204 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482874	SCV001134402	uncertain significance	not provided	2019-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192456	SCV001360592	uncertain significance	not specified	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1937A>G (p.Lys646Arg) results in a conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function, in addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui 2013). The variant allele was found at a frequency of 3.6e-05 in 251204 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00043 in the gnomAD database, which is higher than the expected maximum for a pathogenic variant in MSH6 (0.00014), supporting a benign role for the variant. c.1937A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Lu_2015, Wang_2019, Samuel_2019, Yehia_2018), and one of these individuals had a positive family history for colon cancer (Samuel_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH6, p.K1228fs*2), providing supporting evidence for a benign role (Yehia_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798729	SCV002042038	uncertain significance	Breast and/or ovarian cancer	2021-03-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000482874	SCV002541826	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469131	SCV004197598	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998712	SCV004835633	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 646 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26689913, 30982232), and in an individual affected with endometrial cancer that did not meet Amsterdam II criteria or revised Bethesda guidelines (PMID: 31307542). This variant has been identified in 9/251204 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356893	SCV001552175	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Lys646Arg variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs201096652) as “With Uncertain significance allele”, in ClinVar and Clinvitae (classified as uncertain significance by Invitae, GeneDx and Color Genomics; and likely benign by Ambry Genetics), and COSMIC databases (confirmed somatic in one case of gastric adenocarcinoma). The variant was identified in control databases in 8 of 245948 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 7 of 17248 chromosomes (freq: 0.0004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003) while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, or Finnish populations. The p.Lys646 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.