Submissions for variant NM_000179.3(MSH6):c.1162C>G (p.His388Asp)

gnomAD frequency: 0.00006  dbSNP: rs770386388

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204403	SCV000259508	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000519465	SCV000618483	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter 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)
Ambry Genetics	RCV000574858	SCV000662413	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The p.H388D variant (also known as c.1162C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1162. The histidine at codon 388 is replaced by aspartic acid, an amino acid with similar properties. This variant was classified as benign by authors after being identified in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with AML (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was identified as germline in a cohort of 690 patients with myeloid malignancy (Li ST et al. Leukemia, 2020 Jun;34:1675-1678) and in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574858	SCV001359161	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 388 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with prostate cancer (PMID: 32832836). This variant has been identified in 6/282324 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243887	SCV002512745	uncertain significance	Lynch syndrome 5	2021-07-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4 supporting
Sema4, Sema4	RCV000574858	SCV002535603	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003462366	SCV004195665	uncertain significance	Endometrial carcinoma	2023-07-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997568	SCV004843013	uncertain significance	Lynch syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 388 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/282324 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.