Submissions for variant NM_000179.3(MSH6):c.1133G>A (p.Arg378Lys)

gnomAD frequency: 0.00001  dbSNP: rs587779205

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479933	SCV000567007	uncertain significance	not provided	2021-05-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with early-onset endometrial cancer, who also carried a familial MSH6 nonsense variant (Jori 2015).; This variant is associated with the following publications: (PMID: 22290698, 26517685, 26333163, 15236168)
Ambry Genetics	RCV000569385	SCV000662406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.R378K variant (also known as c.1133G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1133. The arginine at codon 378 is replaced by lysine, an amino acid with highly similar properties. This variant has been reported in a Dutch Caucasian female with endometrioid endometrial cancer and ovarian cancer diagnosed at age 40, who also had a pathogenic MSH6 mutation, p.R482*. This individual's family history met Amsterdam II Criteria (Hendriks YM et al. Gastroenterology. 2004 Jul;127:17-25; Jóri B et al. Oncotarget. 2015 Dec;6:41108-22). This variant has been reported in an individual with tubo-ovarian cancer of mixed histology (Delahunty R et al. J Clin Oncol, 2022 Jun;40:2036-2047). This amino acid position is highly 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	RCV000569385	SCV000690174	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 378 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 an individual affected with ovarian cancer (PMID: 35263119), as well as in individuals affected with Lynch syndrome who also carried a truncating MSH6 variant, p.Arg482*, in cis that could explain the observed phenotype (PMID: 15236168, 26517685). This variant has been identified in 3/250942 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.
Invitae	RCV000629837	SCV000750793	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290538	SCV001478594	uncertain significance	not specified	2022-09-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1133G>A (p.Arg378Lys) results in a 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. One computational prediction method (PON-MMR2) also reports a benign outcome (Niroula_2015). The variant allele was found at a frequency of 1.2e-05 in 250942 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1133G>A has been reported in the literature in a deceased individual affected with Tubo-ovarian cancer without strong evidence for causality (Delahunty_2022). This report do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Co-occurrences with other pathogenic variants have been reported in the UMD database (MSH6 c.1444C>T, p.Arg482*), in an index case with adenocarcinoma in situ on a colon polyp at age 39 and his father affected with colorectal cancer. The mismatch repair function is reported to be MSI-high with IHC demonstrating MSH6 negative/MLH1+MSH2+PMS2+ staining pattern. These findings provide additional supporting evidence for a benign role attributed to this specific variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
All of Us Research Program, National Institutes of Health	RCV003997062	SCV004842991	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 378 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 an individual affected with ovarian cancer (PMID: 35263119), as well as in individuals affected with Lynch syndrome who also carried a truncating MSH6 variant, p.Arg482*, in cis that could explain the observed phenotype (PMID: 15236168, 26517685). This variant has been identified in 3/250942 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	RCV001358106	SCV001553759	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg378Lys variant was identified in 1 of 70 proband chromosomes (frequency: 0.0142857142857143) from individuals or families with endometrial cancer and listed as class 3 variants (Jóri 2015). The variant was also identified in dbSNP (ID: rs587779205) as “With Uncertain significance allele” ,ClinVar (2x, as uncertain significance), Clinvitae (1x, as uncertain significance), UMD-LSDB (2 records , as uncertain significance, co-occurring with MSH6 pathogenic variant [c.1444T>C, p.Arg482X]), Insight Colon Cancer Gene Variant Database (3x, as class 3, ), Insight Hereditary Tumors Database (3x, with "function effect unknown"), databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database and Mismatch Repair Genes Variant databases. The variant was identified in control databases in 3 of 245686 chromosomes at a frequency of 0.000012 (Genome Aggregation Consortium Feb 27, 2017)". The p.Arg378 residue is conserved 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. A co-occurring pathogenic MSH6 variant (c.1444T>C, p.Arg482X) is identified in 1 individual with CRC in our laboratory, increasing the likelihood that p.Arg378Lys variant does not have clinical significance. 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.