Submissions for variant NM_000179.3(MSH6):c.3824G>A (p.Cys1275Tyr)

gnomAD frequency: 0.00006  dbSNP: rs150990541

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656904	SCV000149333	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and glioma (Lu et al., 2015; Tung et al., 2015); This variant is associated with the following publications: (PMID: 23621914, 25186627, 17531815, 21120944, 26689913)
Invitae	RCV000119134	SCV000153848	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115424	SCV000185242	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-29	criteria provided, single submitter	clinical testing	The p.C1275Y variant (also known as c.3824G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3824. The cysteine at codon 1275 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is 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.
Counsyl	RCV000410495	SCV000487844	uncertain significance	Lynch syndrome 5	2015-12-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656904	SCV000601588	uncertain significance	not provided	2019-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115424	SCV000685447	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 1275 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 observed in one individual each affected with breast cancer (PMID: 25186627) and low-grade glioma (PMID: 26689913). This variant has been identified in 8/282376 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	RCV001194392	SCV001363900	uncertain significance	not specified	2019-10-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3824G>A (p.Cys1275Tyr) results in a non-conservative amino acid change located in the ATPase domain of DNA mismatch repair MUTS family domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250998 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3824G>A has been reported in the literature in individuals affected with cancer (Lu_2015, Tung_2014). These reports do 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. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000410495	SCV004018994	likely benign	Lynch syndrome 5	2023-09-05	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: 27363726].
CeGaT Center for Human Genetics Tuebingen	RCV000656904	SCV004033733	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001354737	SCV004835147	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 1275 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 observed in one individual each affected with breast cancer (PMID: 25186627) and low-grade glioma (PMID: 26689913). This variant has been identified in 8/282376 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	RCV001354737	SCV001549424	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Cys1275Tyr variant was identified in 1 of 4316 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Tung 2015). The variant was also identified in dbSNP (ID: rs150990541) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, and three other submitters), Cosmic (1x in Large intestine tissue), and MutDB. The variant was not identified in GeneInsight-COGR, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 9 of 276850 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 9 of 126428 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Cys1275 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.