Submissions for variant NM_000179.3(MSH6):c.1894A>G (p.Lys632Glu)

gnomAD frequency: 0.00001  dbSNP: rs755847154

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198361	SCV000254284	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213164	SCV000274700	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.K632E variant (also known as c.1894A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1894. The lysine at codon 632 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in a female proband with synchronous ovarian and endometrial cancers diagnosed at age 78 that showed absent MSH6 expression by immunohistochemistry while RNA studies demonstrated no impact on splicing when compared to controls (Morak M et al. Eur J Hum Genet, 2022 Sep;30:1051-1059). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000411644	SCV000489236	uncertain significance	Lynch syndrome 5	2016-09-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000213164	SCV000679733	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213164	SCV000908385	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 632 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 5/282122 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781573	SCV000919728	uncertain significance	not specified	2018-01-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1894A>G (p.Lys632Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276694 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (1.8e-05 vs 1.40E-04), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1894A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 uncertain significance.
GeneDx	RCV001580468	SCV001817904	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest this variant does not cause a significant effect on splicing (Morak et al., 2022); Observed in an individual with ovarian and endometrial cancer with concordant tumor studies (Morak et al., 2022); This variant is associated with the following publications: (PMID: 24212087, 17531815, 21120944, 35676339)
Myriad Genetics, Inc.	RCV000411644	SCV004018934	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003996996	SCV004835511	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 632 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282122 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	RCV001357273	SCV001552692	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Lys632Glu variant was not identified in the literature nor was it identified in the UMD-LSDB or Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs755847154) as “With Uncertain significance allele”, and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl and Institute for Biomarker Research). The variant was identified in control databases in 5 of 276694 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 1 of 34406 chromosomes (freq: 0.00003) and European Non-Finnish in 4 of 126322 chromosomes (freq: 0.00003), while not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys632 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer,) 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.