Submissions for variant NM_000249.4(MLH1):c.1514G>A (p.Ser505Asn)

gnomAD frequency: 0.00003  dbSNP: rs771044689

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164523	SCV000215176	likely benign	Hereditary cancer-predisposing syndrome	2021-06-07	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	RCV000205482	SCV000261528	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164523	SCV000292220	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 505 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 colorectal cancer (PMID: 9087566, 23523604). This variant has been identified in 9/282856 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.
GeneDx	RCV000481882	SCV000568568	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and family history of colon cancer, whose colorectal tumor demonstrated microsatellite stability (MSS) (Perez-Cabornero et al., 2013); This variant is associated with the following publications: (PMID: 23588873, 19250818, 31658756, 12799449, 20533529, 22753075, 23523604)
Counsyl	RCV000663072	SCV000786144	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000708926	SCV000838020	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526980	SCV001737771	uncertain significance	not specified	2021-06-05	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1514G>A (p.Ser505Asn) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of 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 3.2e-05 in 251450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1514G>A has been reported in the literature as a VUS in at-least one individual affected with microsatelite stable colorectal cancer (example, Perez-Cabormero_2013) and has been subsequently cited by others. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481882	SCV002046362	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 23523604 (2013), 19250818 (2009), 9087566 (1997)). The frequency of this variant in the general population, 0.00039 (4/10368 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Sema4, Sema4	RCV000164523	SCV002528658	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663072	SCV004018092	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].
Baylor Genetics	RCV000663072	SCV004195039	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-22	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000164523	SCV004228065	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708926	SCV004841032	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 505 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 colorectal cancer (PMID: 9087566, 23523604). This variant has been identified in 9/282856 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.