Submissions for variant NM_000179.3(MSH6):c.1501C>T (p.His501Tyr)

gnomAD frequency: 0.00002  dbSNP: rs779411998

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223633	SCV000276337	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-22	criteria provided, single submitter	clinical testing	The p.H501Y variant (also known as c.1501C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1501. The histidine at codon 501 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in an individuals diagnosed with breast, colorectal and pancreatic cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084; Xiao B et al. Eur J Hum Genet, 2020 11;28:1555-1562; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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	RCV000467079	SCV000551169	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223633	SCV000685197	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 501 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 urothelial carcinoma (PMID: 35372080). This variant has been identified in 10/282596 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.
PreventionGenetics, part of Exact Sciences	RCV004532793	SCV004120321	uncertain significance	MSH6-related disorder	2022-10-19	criteria provided, single submitter	clinical testing	The MSH6 c.1501C>T variant is predicted to result in the amino acid substitution p.His501Tyr. This variant has been reported in an individual with upper tract urothelial carcinoma (Table 2, Guan et al. 2022. PubMed ID: 35372080). This variant is reported in 0.050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48026623-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/232251/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001354875	SCV004839329	uncertain significance	Lynch syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 501 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 urothelial carcinoma (PMID: 35372080). This variant has been identified in 10/282596 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.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093674	SCV001250855	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354875	SCV001549592	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.His501Tyr variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs779411998) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and Color). The variant was identified in control databases in 10 of 282,596 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 10 of 19,946 chromosomes (freq: 0.0005), increasing the likelihood that this variant does not have clinical significance; it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, European, Other or South Asian populations. The p.His501 residue is conserved in mammals but not in more distantly related organisms however four out of five 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) 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.