3-37020432-G-A

Position:

chr3-37020432-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The ENST00000231790.8(MLH1):c.1007G>A(p.Gly336Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G336A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

MLH1
ENST00000231790.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 9.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in ENST00000231790.8

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1007G>A	p.Gly336Asp	missense_variant	11/19	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.1007G>A	p.Gly336Asp	missense_variant	11/19	1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251288

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135840

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:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

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:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

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:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 14, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-related cancers, as well as individuals with a personal or family history of breast/ovarian cancer (Soares et al., 2017; Zidan et al., 2017; Schneider et al., 2018; Ozdemir et al., 2019; Bora et al., 2022); This variant is associated with the following publications: (PMID: 29575718, 28932927, 30238922, 22753075, 28828701, 35220195) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2023	PP3, PM2_moderate -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2022	The p.G336D variant (also known as c.1007G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 1007. The glycine at codon 336 is replaced by aspartic acid, an amino acid with similar properties. This alteration was detected in 1/60 Brazilian patients diagnosed with colorectal cancer, who fulfilled either Bethesda or Amsterdam criteria (Schneider NB et al. Cancer Med. 2018 May;7:2078-2088). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This missense variant replaces glycine with aspartic acid at codon 336 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 29575718) and an individual affected with endometrial cancer (PMID: 30238922). This variant has been identified in 3/251288 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 14, 2023

Variant summary: MLH1 c.1007G>A (p.Gly336Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251288 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1007G>A has been reported in the literature in individuals affected with breast cancer, endometrial cancer, or colorectal cancer without strong evidence of causality (Bora_2022, Ozdemir_2019, Schneider_2018, Soares_2018, Zidan_2017). These reports do not provide unequivocal conclusions about association of the variant with prostate cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces glycine with aspartic acid at codon 336 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 29575718) and an individual affected with endometrial cancer (PMID: 30238922). This variant has been identified in 3/251288 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 336 of the MLH1 protein (p.Gly336Asp). This variant is present in population databases (rs587781750, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28828701, 29575718, 30238922, 35220195). ClinVar contains an entry for this variant (Variation ID: 141442). 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 expected to disrupt MLH1 protein function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;.;.;.;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.9

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.011

D;D;D;D;D;T;D

Sift4G

Benign

0.061

T;D;D;D;D;T;D

Polyphen

0.95

P;.;.;.;.;.;.

Vest4

0.77

MutPred

0.31

Loss of MoRF binding (P = 0.0876);.;.;.;.;.;.;

MVP

0.99

MPC

0.31

ClinPred

0.97

GERP RS

5.2

Varity_R

0.73

gMVP

0.45

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