rs730881739
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3
The NM_000249.4(MLH1):c.976G>A(p.Val326Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V326A) has been classified as Benign.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.976G>A | p.Val326Met | missense_variant | 11/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.976G>A | p.Val326Met | missense_variant | 11/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251374Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 23, 2022 | This missense variant replaces valine with methionine at codon 326 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 colon cancer, whose tumor showed microsatellite stability (PMID: 29212164). This variant has been identified in 1/251374 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2023 | The p.V326M variant (also known as c.976G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 976. The valine at codon 326 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in a cohort of familial colorectal cancer patients undergoing multigene panel testing (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2018 | This variant is denoted MLH1 c.976G>A at the cDNA level, p.Val326Met (V326M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Val326Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val326Met is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Val326Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
MLH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 01, 2023 | The MLH1 c.976G>A variant is predicted to result in the amino acid substitution p.Val326Met. This variant was reported as a variant of uncertain significance in a large cohort of individuals with colon cancer (Raskin et al. 2017. PubMed ID: 29212164, supplementary data). This variant was also described in a patient with suspected Lynch syndrome; however, pathogenic variants were identified in other genes in that individual (Infante et al. 2022. PubMed ID: 36232793). This variant is reported in 1 of ~251,000 alleles in the gnomAD public population database (http://gnomad.broadinstitute.org/variant/3-37061892-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 326 of the MLH1 protein (p.Val326Met). This variant is present in population databases (rs730881739, gnomAD no frequency). This missense change has been observed in individual(s) with colon cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 182522). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 13, 2023 | 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: 27363726]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at