Submissions for variant NM_000249.4(MLH1):c.704A>T (p.Asp235Val)

gnomAD frequency: 0.00001  dbSNP: rs587781505

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129480	SCV000184250	likely benign	Hereditary cancer-predisposing syndrome	2021-05-05	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.
Invitae	RCV000529021	SCV000625188	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 235 of the MLH1 protein (p.Asp235Val). This variant is present in population databases (rs587781505, gnomAD 0.05%). This missense change has been observed in individual(s) with colorectal cancer, hereditary breast and/or ovarian cancer, pancreatic cancer (PMID: 22216297, 23573243, 32068069, 32255556). ClinVar contains an entry for this variant (Variation ID: 141115). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129480	SCV000684862	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 235 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 reported in individuals affected with breast cancer (PMID: 32068069), colorectal cancer (PMID: 2357243, 34172528), and pancreatic ductal adenocarcinoma (PMID: 32255556), but also reported in control individuals (PMID: 22216297, 32980694, 34172528). This variant has been identified in 8/251176 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030626	SCV001193608	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290582	SCV001478665	uncertain significance	not specified	2021-01-31	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.704A>T (p.Asp235Val) 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 3.2e-05 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.704A>T has been reported in the literature in unaffected controls, and individuals with colorectal cancer, in settings of multigene panel testing for PDAC (pancreatic ductal adenocarcinoma) and breast cancer (example, Wei_2011, Hu_2013, Cremin_2020, Kwong_2020). 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. Four 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002285268	SCV002575519	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history of colorectal and other cancers (Hu et al., 2013; Cremin et al., 2020; Kwong et al., 2020); This variant is associated with the following publications: (PMID: 22216297, 22753075, 23573243, 27300552, 32255556, 32566746, 32068069)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153416	SCV003843835	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002285268	SCV004236364	uncertain significance	not provided	2022-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997505	SCV004840896	uncertain significance	Lynch syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 235 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 reported in individuals affected with breast cancer (PMID: 32068069), colorectal cancer (PMID: 2357243, 34172528), and pancreatic ductal adenocarcinoma (PMID: 32255556), but also reported in control individuals (PMID: 22216297, 32980694, 34172528). This variant has been identified in 8/251176 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.