Submissions for variant NM_000179.3(MSH6):c.728G>A (p.Arg243His)

gnomAD frequency: 0.00002  dbSNP: rs370157832

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160655	SCV000211261	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals with ovarian or other cancer (Lu et al., 2015; Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 28912153, 23621914, 26689913, 28002797, 28706299, 21437237, 32566746, 28873162)
Invitae	RCV000459365	SCV000551257	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568587	SCV000662495	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.R243H variant (also known as c.728G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 728. The arginine at codon 243 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an individual diagnosed with ovarian cancer from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568587	SCV000685517	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 243 of the MSH6 protein. Computational prediction 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 reported for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 26689913), colorectal cancer (PMID: 29245953), and unspecified advanced cancer (PMID: 28873162). This variant has been identified in 3/251062 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030489	SCV001193643	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001270441	SCV001450731	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.728G>A (p.Arg243His) missense change has a maximal subpopulation frequency of 0.0062% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-48025850-G-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in an individual with colorectal cancer (PMID: 29245953). It has also been reported somatically in a case of hypermutated pediatric glioblastoma (PMID: 28912153). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230421	SCV003928829	uncertain significance	not specified	2023-04-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.728G>A (p.Arg243His) 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 1.6e-05 in 252042 control chromosomes (gnomAD, Ackay_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728G>A has been reported in the literature in individuals affected with Prostate Cancer (Brady_2022), Ovarian Cancer (Lu_2015), and Breast Cancer (Dorling_2021) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462092	SCV004195652	uncertain significance	Endometrial carcinoma	2023-07-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001270441	SCV004836897	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 243 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 26689913), colorectal cancer (PMID: 29245953), or an unspecified advanced cancer (PMID: 28873162). This variant has been identified in 3/251062 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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.