Submissions for variant NM_000179.3(MSH6):c.3607C>A (p.His1203Asn)

gnomAD frequency: 0.00001  dbSNP: rs876660882

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457877	SCV000551305	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000490961	SCV000580230	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The p.H1203N variant (also known as c.3607C>A), located in coding exon 7 of the MSH6 gene, results from a C to A substitution at nucleotide position 3607. The histidine at codon 1203 is replaced by asparagine, an amino acid with similar properties. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer. 2015 Jan;121:25-33). This alteration was also detected in the germline of a patient diagnosed with an MLH1/PMS2-deficient colon cancer at age 50; the tumor was identified to have double somatic MLH1 mutations (Pearlman R et al. J Med Genet. 2019 07;56:462-470). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000490961	SCV000685420	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with asparagine at codon 1203 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 been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 2/282784 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.
Sema4, Sema4	RCV000490961	SCV002528050	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496783	SCV002814367	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-07-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003148746	SCV003837183	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Baylor Genetics	RCV003463944	SCV004197712	uncertain significance	Endometrial carcinoma	2023-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003148746	SCV004221234	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 25186627 (2015)), and colorectal cancer (PMID: 30877237 (2019)). The frequency of this variant in the general population, 0.0000071 (2/282784 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004001861	SCV004835105	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with asparagine at codon 1203 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 hereditary cancer in the literature. This variant has been identified in 2/282784 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.