3-37042309-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000249.4(MLH1):c.1709A>G(p.Asn570Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251190Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135764
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1458314Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 725770
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74342
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:3Benign:1
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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]. -
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not provided Uncertain:2
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: 25980754, 24728327, 25085752, 36243179, 25617771, 12799449, 20533529, 22753075) -
The MLH1 c.1709A>G (p.Asn570Ser) variant has been reported in the published literature in individuals with Lynch syndrome associated cancers (PMID: 25980754 (2015), 25617771 (2015)), as well as reportedly healthy individuals (PMID: 24728327 (2014), 36243179 (2022)). In a large breast cancer association study, this variant was seen both in individuals with cancer and in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1)). The frequency of this variant in the general population, 0.00024 (6/24956 chromosomes in African/African American 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. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This missense variant replaces asparagine with serine at codon 570 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 an individual affected with endometrial cancer whose tumor displayed normal mismatch repair protein expression via immunohistochemistry (PMID: 25617771), and and individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/282582 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. -
not specified Uncertain:1Other:1
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Variant summary: MLH1 c.1709A>G (p.Asn570Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1709A>G has been reported in the literature in individuals affected with Lynch syndrome-associated cancers without strong evidence of causality (e.g. Frolova_2015, Yurgelun_2015, Xu_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 134658). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
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MLH1-related disorder Uncertain:1
The MLH1 c.1709A>G variant is predicted to result in the amino acid substitution p.Asn570Ser. This variant has been reported in at least three individuals with Lynch syndrome-associated cancers (Frolova et al. 2015. PubMed ID: 25617771; Yurgelun et al. 2015. PubMed ID: 25980754; Okawa et al. 2023. PubMed ID: 36243179). IHC studies in one of the reported individuals were normal (Frolova et al. 2015. PubMed ID: 25617771). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. 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 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at