Submissions for variant NM_000179.3(MSH6):c.3450A>C (p.Leu1150Phe)

dbSNP: rs762134820

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213324	SCV000279277	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3450A>C at the cDNA level, p.Leu1150Phe (L1150F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Leu1150Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1150Phe occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the ATP binding motif (Kariola 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Leu1150Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456211	SCV000551248	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-26	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 1150 of the MSH6 protein (p.Leu1150Phe). This variant is present in population databases (rs762134820, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 234462). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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	RCV000491638	SCV000580209	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The p.L1150F variant (also known as c.3450A>C), located in coding exon 6 of the MSH6 gene, results from an A to C substitution at nucleotide position 3450. The leucine at codon 1150 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000491638	SCV000911940	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1150 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 2/251420 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254691	SCV002526003	uncertain significance	Lynch syndrome 5	2022-05-26	criteria provided, single submitter	clinical testing	The MSH6 c.3450A>C (p.Leu1150Phe) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance.
Baylor Genetics	RCV003463611	SCV004195629	uncertain significance	Endometrial carcinoma	2023-08-02	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535554	SCV001749531	not provided	Mismatch repair cancer syndrome 1; Lynch syndrome 5		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-10-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.