Submissions for variant NM_000249.4(MLH1):c.1487C>G (p.Pro496Arg)

dbSNP: rs63750226

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627722	SCV000254351	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000221321	SCV000273311	benign	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Counsyl	RCV000409591	SCV000488536	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000483364	SCV000565156	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	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: 22290698, 30093976, 35098669, 29684080, 17250665, 32068069, 22753075, 12799449, 20533529)
Color Diagnostics, LLC DBA Color Health	RCV000221321	SCV000684749	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 496 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 reported for this variant. This variant has been reported in an individual affected with endometrial cancer, whose tumor demonstrated microsatellite stability, normal MLH1 expression and lack of MSH2 expression (PMID: 17250665), as well as in two individuals affected with breast cancer (PMID: 32068069). This variant has been identified in 16/251484 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.
Fulgent Genetics, Fulgent Genetics	RCV000764493	SCV000895564	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2022-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228178	SCV002511440	uncertain significance	not specified	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1487C>G (p.Pro496Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251484 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (6.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.1487C>G has been reported in the literature in individuals affected with colorectal cancer, lung cancer and breast and/or ovarian cancer (Bianchi_2007, Chan_2018, Kwong_2020). These reports 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. Six ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000221321	SCV002528654	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409591	SCV004018188	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483364	SCV004220072	uncertain significance	not provided	2022-11-29	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00043 (8/18394 chromosomes in East Asian 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 individuals with colon cancer (PMID: 29684080 (2018)), lung cancer (PMID: 30093976 (2018)), endometrial cancer (PMID: 17250665 (2007)), and personal/family history of breast/ovarian cancer (PMID: 32068069 (2020)). 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 deleterious or benign. 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	RCV003997114	SCV004841022	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 496 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 reported for this variant. This variant has been reported in an individual affected with endometrial cancer, with tumor showing microsatellite stability, normal MLH1 expression and lack of MSH2 expression (PMID: 17250665) and two individuals affected with breast cancer (PMID: 32068069). This variant has been identified in 16/251484 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.