Submissions for variant NM_002439.5(MSH3):c.1394A>G (p.Tyr465Cys)

gnomAD frequency: 0.00032  dbSNP: rs35009542

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808688	SCV000948803	uncertain significance	not provided	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 465 of the MSH3 protein (p.Tyr465Cys). This variant is present in population databases (rs35009542, gnomAD 0.04%). This missense change has been observed in individual(s) with endometrial cancer and/or polyposis (PMID: 31243857, 32634176). ClinVar contains an entry for this variant (Variation ID: 653005). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001011315	SCV001171620	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.Y465C variant (also known as c.1394A>G), located in coding exon 9 of the MSH3 gene, results from an A to G substitution at nucleotide position 1394. The tyrosine at codon 465 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected as heterozygous in patient with greater than 9 adenomatous and 19 hyperplastic colon polyps at age 53 with no family history of polyposis or colorectal cancer. No other alterations in MSH3 were reportedly detected in this patient (Terradas M et al. Hum Mutat, 2019 11;40:1910-1923). This alteration was also detected in a patient with endometrial cancer who had a first degree relative with ovarian cancer (Singh AK et al. PLoS One, 2020 Jul;15:e0235613). This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). 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.
GeneDx	RCV000808688	SCV002499839	uncertain significance	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Observed in individuals with endometrial cancer, renal cancer, or colorectal polyps (PMID: 32634176, 31243857, 37095444); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31243857, 32634176, 21153778, 29641532, 37095444)
Sema4, Sema4	RCV001011315	SCV002535950	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268297	SCV002550491	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325218	SCV004031251	uncertain significance	Familial adenomatous polyposis 4	2023-10-18	criteria provided, single submitter	clinical testing	The MSH3 c.1394A>G (p.Tyr465Cys) missense change has a maximum subpopulation frequency of 0.043% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in one individual with endometrial cancer (PMID: 32634176). In a case-control study, this variant has been reported in 1 of 431 individuals with polyposis and 1 of 4300 controls (OR=10, PMID: 31243857). It has also been identified in 1 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003467426	SCV004196981	uncertain significance	Endometrial carcinoma	2024-03-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000808688	SCV004221037	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	The MSH3 c.1394A>G (p.Tyr465Cys) variant has been reported in the published literature in individuals with polyposis (PMID: 31243857 (2019)), renal cell carcinoma (PMID: 37095444 (2023)), and endometrial cancer (PMID: 32634176 (2020)). Additionally, this variant has been identified in reportedly healthy individuals (PMIDs: 31243857 (2019), 29641532 (2018)). The frequency of this variant in the general population, 0.00045 (23/50742 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV005036178	SCV005666181	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751722	SCV005352240	uncertain significance	MSH3-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The MSH3 c.1394A>G variant is predicted to result in the amino acid substitution p.Tyr465Cys. This variant has been reported in an individual with polyposis (Table S1, Terradas et al. 2019. PubMed ID: 31243857) and in an individual with endometrial cancer (Table 1, Singh et al. 2020. PubMed ID: 32634176). However this variant was also observed in a control cohort (UK10K_DNArep in Supplement, Pritchard AL et al. 2018. PubMed ID: 29641532). This variant is reported in 0.043% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/653005/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.