Submissions for variant NM_000249.4(MLH1):c.626A>G (p.Asn209Ser)

gnomAD frequency: 0.00011  dbSNP: rs150478207

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132489	SCV000187583	likely benign	Hereditary cancer-predisposing syndrome	2019-10-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000200318	SCV000254371	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000480315	SCV000566134	likely benign	not provided	2019-09-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29684080, 23047549)
Counsyl	RCV000662374	SCV000784768	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000708915	SCV000837999	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480315	SCV000889401	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00028 (7/24968 chromosomes in African/African-American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 23047549 (2012)) and thyroid cancer (PMID: 29684080 (2018)). In a large scale breast cancer association study, the variant was observed individuals with breast cancer cases as well as in unaffected study control individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). 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.
Color Diagnostics, LLC DBA Color Health	RCV000132489	SCV000902912	likely benign	Hereditary cancer-predisposing syndrome	2016-04-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000662374	SCV001136380	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804854	SCV002051078	uncertain significance	not specified	2022-06-23	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.626A>G (p.Asn209Ser) results in a conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251242 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00071), allowing no conclusion about variant significance. c.626A>G has been reported in the literature in individuals affected with (tubo)-ovarian cancer (Pal_2012, Delahunty_2022). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=3) or VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001804854	SCV002068065	uncertain significance	not specified	2020-04-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.626A>G, in exon 8 that results in an amino acid change, p.Asn209Ser. This sequence change has been previously described in a patient with ovarian cancer (PMID: 23047549). This sequence change has been described in the gnomAD database with a low population frequency of 0.0067% (dbSNP rs150478207). The p.Asn209Ser change affects a moderately conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. The p.Asn209Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn209Ser change remains unknown at this time.
Sema4, Sema4	RCV000132489	SCV002528762	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662374	SCV004018109	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003398776	SCV004119871	uncertain significance	MLH1-related condition	2024-01-25	criteria provided, single submitter	clinical testing	The MLH1 c.626A>G variant is predicted to result in the amino acid substitution p.Asn209Ser. This variant has been reported in individuals with ovarian or breast cancer (Table S1, Pal et al. 2012. PubMed ID: 23047549; Table S1, Hu et al. 2022. PubMed ID: 35449176). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142980/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662374	SCV004171471	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-16	criteria provided, single submitter	clinical testing	The MLH1 c.626A>G (p.Asn209Ser) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with ovarian cancer (PMID: 23047549). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.