rs267607727
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001167618.3(MLH1):c.-422G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,370 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 Likely pathogenic (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
MLH1
NM_001167618.3 5_prime_UTR_premature_start_codon_gain
NM_001167618.3 5_prime_UTR_premature_start_codon_gain
Scores
6
2
1
Clinical Significance
Conservation
PhyloP100: 9.42
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.48
PP5
Variant 3-37001049-G-A is Pathogenic according to our data. Variant chr3-37001049-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90138.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37001049-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-37001049-G-A is described in Lovd as [Benign].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.94e-7 AC: 1AN: 1440370Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 717924
GnomAD4 exome
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1440370
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27
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0
AN XY:
717924
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 12, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [PMID: 26249686, Myriad internal data]. - |
Lynch syndrome 1 Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Mar 09, 2018 | Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.968 - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2021 | Published functional studies demonstrate a damaging effect: reduced protein expression and MMR repair activity compared to wild type (Ellison 2004, Hinrichsen 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family histories consistent with Lynch syndrome (Taylor 2003, Tournier 2008); This variant is associated with the following publications: (PMID: 19224586, 15475387, 23403630, 22290698, 25525159, 14635101, 18561205, 31784484) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2021 | The p.G101D variant (also known as c.302G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 302. The glycine at codon 101 is replaced by aspartic acid, an amino acid with similar properties. Two in vitro functional studies demonstrated reduced MMR function for p.G101D when compared to wild-type MLH1 in yeast (Ellison AR et al. Nucleic Acids Res. 2004 ; 32(18):5321-38; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). The Hinrichsen study also found decreased expression (10-20% relative expression) for this variant when compared to wild-type. Based on internal structural analysis, this variant is highly destabilizing and resides in a known motif within close proximity to known pathogenic variants (Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug; 71(Pt 8):981-5; Hol WG et al. Nature. 1978 Jun; 273(5662):443-6). The p.G101D variant was also identified in a family meeting Bethesda guidelines (Taylor CF et al. Hum. Mutat. 2003 Dec; 22(6):428-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at