Variant 3-37048583-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The MLH1 c.1963A>T variant is predicted as a missense variant, p.(Ile655Phe). It is extremely rare (<1 in 50,000 alleles) in gnomAD v.2.1.1 using the noncancer dataset and in gnomAD v4.1. Its MAPP+PolyPhen-2 prior probability for pathogenicity is <0.11 as per http://priors.hci.utah.edu/PRIORS. Therefore, this variant is classified as a variant of unknown significance. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA031690/MONDO:0005835/115

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

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]

MLH1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1963A>T	p.Ile655Phe	missense_variant	17/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1963A>T	p.Ile655Phe	missense_variant	17/19	1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251262

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2023

This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs55907433, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 655 of the MLH1 protein (p.Ile655Phe). ClinVar contains an entry for this variant (Variation ID: 1000222). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.010

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.67

D;.;.;.;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.97

D;D;.;.;.;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.57

D;D;D;D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-0.030

N;.;.;.;.;.

MutationTaster

Benign

0.95

N;N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.033

D;D;D;D;D;D

Sift4G

Benign

0.12

T;T;T;T;T;D

Polyphen

0.12

B;.;.;.;.;.

Vest4

0.64

MutPred

0.67

Loss of catalytic residue at L660 (P = 0.0539);.;.;.;.;.;

MVP

0.94

MPC

0.12

ClinPred

0.24

GERP RS

0.59

Varity_R

0.34

gMVP

0.52

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over