Submissions for variant NM_000179.3(MSH6):c.2855T>C (p.Leu952Pro)

gnomAD frequency: 0.00001  dbSNP: rs587781743

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129947	SCV000184766	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	clinical testing	The p.L952P variant (also known as c.2855T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2855. The leucine at codon 952 is replaced by proline, an amino acid with similar properties. 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.
Invitae	RCV000629697	SCV000750653	likely benign	Hereditary nonpolyposis colorectal neoplasms	2022-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582602	SCV001821301	uncertain significance	not specified	2021-08-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2855T>C (p.Leu952Pro) results in a non-conservative amino acid change in 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 4e-06 in 250318 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2855T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997536	SCV004824883	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 952 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 2/281710 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	RCV000502711	SCV000592615	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Leu952Pro variant was not identified in the literature nor was it identified in the dbSNP, COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database or UMD databases. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 1 of 120320 chromosomes (frequency: 0.8.31E-06) (or 1 individuals) from a population of European (Non-Finnish), and none from East Asian, Other, African, Latino, South Asian, or European (Finnish) individuals; and the ClinVar database (classification uncertain significance by Ambry Genetics); and in the Clinvitae database (classification uncertain significance).The p.Leu952 residue is not conserved in mammals and lower organisms, 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, HumanSpliceFinder) 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 unknown significance.