rs63751608
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.1721T>C(p.Leu574Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L574V) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 7.16
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 16 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000249.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
?
Variant 3-37042321-T-C is Pathogenic according to our data. Variant chr3-37042321-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89846.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37042321-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-37042321-T-C is described in Lovd as [Benign]. Variant chr3-37042321-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1721T>C | p.Leu574Pro | missense_variant | 15/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1721T>C | p.Leu574Pro | missense_variant | 15/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Lynch syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | May 01, 2018 | MLH1 NM_000249.3:c.1721T>C has a 95.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. - |
Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Jun 21, 2019 | Abrogated function & co-segregation with disease - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MLH1 protein function (PMID: 21404117, 23403630, 9697702, 17510385, 10037723, 15864295, 12810663, 18094436, 11427529). This variant has been observed in several individuals affected with Lynch syndrome-related cancers (PMID: 7757073, 15365995), and was shown to segregate with colon cancer in a family (PMID: 7757073). ClinVar contains an entry for this variant (Variation ID: 89846). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 574 of the MLH1 protein (p.Leu574Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2021 | The p.L574P variant (also known as c.1721T>C), located in coding exon 15 of the MLH1 gene, results from a T to C substitution at nucleotide position 1721. The leucine at codon 574 is replaced by proline, an amino acid with similar properties. This alteration was identified as somatic in an individual with a second pathogenic somatic alteration and whose Lynch-related tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 expression on immunohistochemistry with negative MLH1 promoter hypermethylation (Ambry internal data). This alteration co-segregates with disease in a Korean family that meets Amsterdam criteria (Han HJ et al. Hum Mol Genet, 1995 Feb;4:237-42) and was also identified in a 32-year-old Korean male with colorectal cancer from a cohort of 141 HNPCC families (Shin YK et al. Hum Mutat, 2004 Oct;24:351). Functional studies demonstrate reduced MMR activity relative to wild-type MLH1, a dominant negative mutator effect in yeast, aberrant interaction with PMS2 that is similar to pathogenic controls, and reduced MLH1 protein stability/expression (Shimodaira H et al. Nat Genet, 1998 Aug;19:384-9; Guerrette S et al. J Biol Chem, 1999 Mar;274:6336-41; Kondo E et al. Cancer Res, 2003 Jun;63:3302-8; Takahashi M et al. Cancer Res, 2007 May;67:4595-604; Fan Y et al. Clin Cancer Res, 2007 Dec;13:7515-21; Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;.;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
P;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.007);.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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