Submissions for variant NM_000249.4(MLH1):c.945C>G (p.His315Gln)

gnomAD frequency: 0.00004  dbSNP: rs587779959

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115488	SCV000149397	uncertain significance	not provided	2023-09-13	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; This variant is associated with the following publications: (PMID: 26845104, 25503501, 22753075, 28259476, 32547938)
Invitae	RCV000524323	SCV000166258	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 315 of the MLH1 protein (p.His315Gln). This variant is present in population databases (rs587779959, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, colon polyps and prostate cancer (PMID: 25503501, 26845104, 28259476, 32547938). ClinVar contains an entry for this variant (Variation ID: 127623). 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 not expected to disrupt MLH1 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000122978	SCV000266183	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000568893	SCV000662014	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The p.H315Q variant (also known as c.945C>G), located in coding exon 11 of the MLH1 gene, results from a C to G substitution at nucleotide position 945. The histidine at codon 315 is replaced by glutamine, an amino acid with highly similar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes. (Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8). In a cohort of 1462 individuals referred to the University of Washington for their BROCA or ColoSeq multigene panel testing, this alteration was detected in an individual with colon polyps and a family history of colon and pancreatic cancer, and is classified by the authors as a variant of uncertain significance (Shirts BH et al. Genet. Med. 2016 Oct;18(10):974-81). This alteration was also observed in an individual with metastatic castration-resistant prostate cancer (Annala M et al. Eur. Urol., 2017 07;72:34-42). In another study, this alteration was identified in 1/711 breast cancer patients and 0/492 healthy controls (Nikitin AG et al. Front Oncol. 2020 May;10:666). 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.
Color Diagnostics, LLC DBA Color Health	RCV000568893	SCV000911072	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 315 of the MLH1 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 performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 32547938), prostate cancer (PMID: 28259476), as well as in an individual affected with colon polyps with family history of colon and pancreatic cancer (PMID: 26845104). This variant has been identified in 5/282808 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253192	SCV001428786	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-06-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115488	SCV001470545	uncertain significance	not provided	2020-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553749	SCV001774739	uncertain significance	not specified	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.945C>G (p.His315Gln) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.945C>G has been reported in the literature as a VUS in settings of multigene cancer panel testing in cohorts of individuals with a family/personal history of cancer (example, Shirts_2015), breast cancer (example, Maxwell_2015, Nikitin_2020) and metastatic castration-resistant prostate cancer (mCRPC) (example, Annala_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000115488	SCV004185048	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001253192	SCV004195058	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000122978	SCV004840928	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 315 of the MLH1 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). 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 been reported in an individual affected with breast cancer (PMID: 25503501), as well as in an individual with family history of colon and pancreatic cancer (PMID: 26845104). This variant has been identified in 5/282808 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.