Submissions for variant NM_000179.3(MSH6):c.359T>C (p.Ile120Thr)

gnomAD frequency: 0.00003  dbSNP: rs775971872

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214442	SCV000273040	likely benign	Hereditary cancer-predisposing syndrome	2019-03-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000589961	SCV000279267	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with colon cancer whose tumor showed microsatellite instability and loss of MLH1 protein expression and in an individual with adrenocortical carcinoma (PMID: 23354634, 32156018); This variant is associated with the following publications: (PMID: 26457233, 30212499, 32156018, 23354634)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589961	SCV000695877	uncertain significance	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121410 (1/60705), all in the Latino cohort, 2/11578 (1/5789), which does not significantly exceed the predicted maximum expected allele frequency for a pathogenic MSH6 variant of 1/7037. The variant of interest has been reported in affected individuals via publications, although with limited information, although one pt was indicated to have the expression of MLH1 to be absent. However, no reputable databases or clinical laboratories have cited the variant of interest. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629813	SCV000750769	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214442	SCV000911036	likely benign	Hereditary cancer-predisposing syndrome	2016-09-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000986701	SCV001135781	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000708853	SCV001450732	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.359T>C (p.Ile120Thr) missense change has a maximal subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48018164-T-C). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in a family with Lynch syndrome (PMID: 23354634). It has also been reported in a patient with adrenocortical carcinoma whom also harbored the TP53 p.Arg337His variant (PMID: 32156018). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589961	SCV001469571	uncertain significance	not provided	2024-10-21	criteria provided, single submitter	clinical testing	The MSH6 c.359T>C (p.Ile120Thr) variant has been reported in the published literature in a family with Lynch syndrome (PMID: 23354634 (2012)), as well as an individual with an adrenocortical tumor (PMID: 32156018 (2020)). The frequency of this variant in the general population, 0.00011 (4/35440 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV003462406	SCV004195541	uncertain significance	Endometrial carcinoma	2024-03-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589961	SCV005875630	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	The MSH6 c.359T>C; p.Ile120Thr variant (rs775971872, ClinVar Variation ID: 229725) is reported in the literature in a family meeting Amsterdam criteria (Wielandt 2012) and in an individual with adrenocortical tumor who also carried a TP53 germline mutation (Brondani 2020). This variant is observed in the general population with an overall allele frequency of 0.002% (6/282894 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.093). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Brondani VB et al. High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53. Cancers (Basel). 2020 Mar 7;12(3):621. PMID: 32156018. Wielandt AM et al. [Lynch syndrome: selection of families by microsatellite instability and immunohistochemistry]. Rev Med Chil. 2012 Sep;140(9):1132-9. Spanish. PMID: 23354634.