Submissions for variant NM_000249.4(MLH1):c.1154G>A (p.Arg385His)

gnomAD frequency: 0.00005  dbSNP: rs63750430

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128876	SCV000172733	likely benign	Hereditary cancer-predisposing syndrome	2020-09-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232561	SCV000284007	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 385 of the MLH1 protein (p.Arg385His). This variant is present in population databases (rs63750430, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 140759). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Counsyl	RCV000409286	SCV000488610	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000657135	SCV000570352	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate MLH1 protein expression and mismatch repair (MMR) activity similar to wildtype (PMID: 37224528); Observed in individuals with colorectal, breast, or other cancers, as well as in unaffected controls is a study of biliary tract cancer (PMID: 36243179, 27498913, 30982232, 35223509, 35264596, 36627197, 35449176); This variant is associated with the following publications: (PMID: 31391288, 27149842, 33042626, 31248605, 36215471, 27498913, 35223509, 30982232, 35264596, 36627197, 37224528, Abudabbous2023[CaseReport], 36243179, 35449176)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657135	SCV000601346	uncertain significance	not provided	2020-01-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764490	SCV000895561	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128876	SCV000911263	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484459	SCV000919660	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1154G>A (p.Arg385His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.1154G>A has been reported in the literature as a VUS in settings of multi-gene testing in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome, and in individuals affected with prostate and other cancers (e.g. Wang_2019, Wei_2019, Li_2021, Fanale_2022). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=9) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000409286	SCV001136401	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000409286	SCV001307794	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Myriad Genetics, Inc.	RCV000409286	SCV004018138	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000409286	SCV004171468	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-16	criteria provided, single submitter	clinical testing	The MLH1 c.1154G>A (p.Arg385His) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in one individual with Lynch syndrome-related colorectal cancer (PMID: 35223509), as well as in individuals with prostate cancer (PMID: 31248605), lung adenocarcinoma (PMID: 35280419), and familial breast/ovarian cancer (PMID: 30982232). 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.
Baylor Genetics	RCV000409286	SCV004195059	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657135	SCV004236360	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997466	SCV004840964	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 385 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249936	SCV001423878	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing