Submissions for variant NM_000179.3(MSH6):c.3601C>T (p.Leu1201Phe)

gnomAD frequency: 0.00001  dbSNP: rs182024561

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220632	SCV000273196	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The p.L1201F variant (also known as c.3601C>T), located in coding exon 7 of the MSH6 gene, results from a C to T substitution at nucleotide position 3601. The leucine at codon 1201 is replaced by phenylalanine, an amino acid with highly similar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000685624	SCV000813109	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1201 of the MSH6 protein (p.Leu1201Phe). This variant is present in population databases (rs182024561, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of MSH6-related conditions (PMID: 21520333, 33471991). ClinVar contains an entry for this variant (Variation ID: 229845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH6 protein function. This variant disrupts the p.Leu1201 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29875428; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV000220632	SCV000908423	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1201 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a breast cancer case-control study, this variant has been observed in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251436 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.
Baylor Genetics	RCV003462412	SCV004195732	uncertain significance	Endometrial carcinoma	2023-06-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997777	SCV004835099	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1201 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a breast cancer case-control study, this variant has been observed in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251436 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.