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rs1799977

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM2PM5BP4BP6_Very_Strong

The NM_000249.4(MLH1):c.655A>C(p.Ile219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I219V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 missense

Scores

8
11

Clinical Significance

Benign reviewed by expert panel B:1

Conservation

PhyloP100: 2.05
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 Likely_benign. 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 chr3-37012077-A-G is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.30772832).
BP6
Variant 3-37012077-A-C is Benign according to our data. Variant chr3-37012077-A-C is described in ClinVar as [Benign]. Clinvar id is 90305.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37012077-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.655A>C p.Ile219Leu missense_variant 8/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.655A>C p.Ile219Leu missense_variant 8/191 NM_000249.4 P1P40692-1

Frequencies

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

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Lynch syndrome Benign:1
Benign, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.060
Cadd
Benign
19
Dann
Uncertain
0.98
DEOGEN2
Uncertain
0.51
D;.
Eigen
Benign
-0.046
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Benign
-0.41
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.95
N;N
REVEL
Uncertain
0.50
Sift
Benign
0.32
T;T
Sift4G
Benign
0.52
T;T
Polyphen
0.025
B;.
Vest4
0.43
MutPred
0.42
Loss of catalytic residue at I219 (P = 0.0537);.;
MVP
0.83
MPC
0.10
ClinPred
0.49
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1799977; hg19: chr3-37053568; API