chr3-37048559-G-A

Position:

chr3-37048559-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000249.4(MLH1):c.1939G>A(p.Val647Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.04

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:

MLH1 (HGNC:):

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29820117).

BP6

Variant 3-37048559-G-A is Benign according to our data. Variant chr3-37048559-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 89952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1939G>A	p.Val647Met	missense_variant	17/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1939G>A	p.Val647Met	missense_variant	17/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251310

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000730

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000416

Hom.:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2023	The p.V647M variant (also known as c.1939G>A) is located in coding exon 17 of the MLH1 gene. This alteration results from a G to A substitution at nucleotide position 1939. The valine at codon 647 is replaced by methionine, an amino acid with highly similar properties. This alteration has been identified in identified in 1/369 Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835) as well as in one proband, diagnosed with 1-100 colon polyps at age 71, with a family history of colon cancer (Rohlin A et al. Fam. Cancer, 2017 Apr;16:195-203). This amino acid position is well conserved in mammals but not all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2023	This missense variant replaces valine with methionine at codon 647 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a Swedish Lynch syndrome family (PMID: 27601186), and in individuals affected with prostate cancer (PMID: 16963262), breast cancer (PMID: 27328445), and colorectal cancer (PMID: 27601186). This variant has been identified in 30/282696 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.97

D;D;.;.;.;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

L;.;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.15

T;D;D;D;D;D

Sift4G

Benign

0.20

T;T;T;T;T;T

Polyphen

0.70

P;.;.;.;.;.

Vest4

0.58

MVP

0.84

MPC

0.16

ClinPred

0.067

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.47

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