ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2561_2562delinsTT (p.Lys854Ile) (rs587780673)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122958 SCV000166222 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-03-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000214497 SCV000273126 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-15 criteria provided, single submitter clinical testing The c.2561_2562delAGinsTT variant (also known as p.K854I), located in coding exon 4 of the MSH6 gene, results from an in-frame deletion of AG and insertion of TT at nucleotide positions 2561 to 2562. This results in the substitution of the lysine residue for an isoleucine residue at codon 854, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000214497 SCV000685295 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-08 criteria provided, single submitter clinical testing This missense variant replaces lysine with isoleucine at codon 854 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant is reported as two single nucleotide variants identified in 105/280696 chromosomes for chr2.GRCh37:g.48027683A>T and 22/280654 chromosomes for chr2.GRCh37:g.48027684G>T 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 RCV001193127 SCV001361764 uncertain significance not specified 2019-05-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2561_2562delinsTT (p.Lys854Ile) results in a non-conservative amino acid change in 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 3.6e-06 in 280654 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2561_2562delinsTT, has been reported in the literature in individuals affected with breast cancer or colon cancer (Zick_2015, Ghazani_2017). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=2), Likely benign (n=1)). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284519 SCV001470354 likely benign not provided 2020-04-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355264 SCV001550095 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Lys854Ile variant was identified in 2 of 80 proband chromosomes (frequency: 0.03) from individuals or families with breast cancer (Zick 2015). The variant was also identified in dbSNP (ID: rs587780673) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics and Color). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Lys854 residue is conserved across mammals and other organisms, and four out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) 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.

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