3-37007004-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000249.4(MLH1):​c.394G>T​(p.Asp132Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D132H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.67
Variant links:
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 Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37007004-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.394G>T p.Asp132Tyr missense_variant Exon 5 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.394G>T p.Asp132Tyr missense_variant Exon 5 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Jan 08, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.D132Y variant (also known as c.394G>T), located in coding exon 5 of the MLH1 gene, results from a G to T substitution at nucleotide position 394. The aspartic acid at codon 132 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.4
M;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.2
D;D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.91
MutPred
0.42
Gain of catalytic residue at D132 (P = 0.0062);.;.;
MVP
0.97
MPC
0.45
ClinPred
0.98
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.78
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-37048495; API