3-37042330-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000249.4(MLH1):c.1730C>T(p.Ser577Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000194 in 1,598,554 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S577S) has been classified as Pathogenic.
Frequency
Consequence
NM_000249.4 missense, splice_region
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: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251202Hom.: 1 AF XY: 0.0000589 AC XY: 8AN XY: 135766
GnomAD4 exome AF: 0.0000187 AC: 27AN: 1446444Hom.: 1 Cov.: 29 AF XY: 0.0000180 AC XY: 13AN XY: 720782
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | May 22, 2024 | The MLH1 c.1730C>T (p.Ser577Leu) missense change has a maximum subpopulation frequency of 0.07% 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 individuals with Lynch syndrome-associated tumors (PMID: 27601186; 28767289). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 14, 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: 25085752]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 13, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2023 | Observed in individuals with a personal or family history of Lynch syndrome-associated cancers and in a healthy individual undergoing whole genome sequencing (Chao et al., 2008; Bodian et al., 2014; Lagerstedt-Robinson et al., 2016; Shindo et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.1007C>T; p.(Ser336Leu); This variant is associated with the following publications: (PMID: 33471991, 25186627), 30982232, 32914570, 31391288, 24728327, 27601186, 18383312, 28767289, 33281875, 32959997, 27535533, 12799449, 20533529, 22753075) - |
not specified Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | May 06, 2015 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2022 | Variant summary: MLH1 c.1730C>T (p.Ser577Leu) results in a non-conservative amino acid change located in the 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251202 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote.The variant, c.1730C>T, has been reported in the literature in individuals affected with colorectal cancer and other tumor phenotypes that belong to the Lynch Syndrome tumor spectrum (example: Chao_2008, Lagerstedt-Robinson_2016, Toh_2018, Li_2020, Jiang_2020, Shindo_2017 etc.). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The variant has been also reported in the literature in multiple individuals affected with Breast Cancer (example: Tung_2015, Wang_2019 etc.). However, a recent large-scale Breast Cancer study reported the variant in 13/60466 BrC cases and 13/53461 controls, i.e. with a calculated odds ratio of 0.88, which suggests that this variant is not associated with a risk for Breast Cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as VUS (n=8), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2020 | This alteration is classified as 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 20, 2023 | This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast, and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997, 33471991), as well as in multiple unaffected individuals reported in pancreatic cancer and breast cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 17/282594 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. - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2024 | This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997) and an unaffected individual in a pancreatic cancer case-control study (PMID: 32980694). However, this variant has not shown a significant association with breast cancer in a large case-control study, with an odds ratio reported at 0.884 (95% confidence interval: 0.41 to 1.907, PMID: 33471991). This variant has been identified in 17/282594 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. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at