3-37025734-A-G

Position:

chr3-37025734-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000249.4(MLH1):c.1136A>G(p.Tyr379Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:8B:5

Conservation

PhyloP100: 4.43

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 Benign. Variant got -8 ACMG points.

BP6

Variant 3-37025734-A-G is Benign according to our data. Variant chr3-37025734-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 142276.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37025734-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1136A>G	p.Tyr379Cys	missense_variant	12/19	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.1136A>G	p.Tyr379Cys	missense_variant	12/19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251454

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000615

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151294

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000639

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:8Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2024	The MLH1 c.1136A>G (p.Tyr379Cys) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 26898890 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)), ovarian cancer (PMID: 23047549 (2012)), suspected Lynch syndrome (PMIDs: 21404117 (2011), 14635101 (2003)), kidney cancer (PMID: 29684080 (2018)), and mesothelioma (PMID: 28687356 (2017)). This variant has also been observed in reportedly healthy individuals (PMID: 33471991 (2021)). Experimental studies indicate this variant has nearly no effect on MLH1 DNA repair activity (PMID: 32849802 (2020)). The frequency of this variant in the general population, 0.00014 (5/35438 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2019	This variant is denoted MLH1 c.1136A>G at the cDNA level, p.Tyr379Cys (Y379C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has been observed in individuals with colorectal cancer, gastric cancer, ovarian cancer, renal cancer, breast cancer, sarcoma, and malignant pleural mesothelioma (Taylor 2003, Hardt 2011, Pal 2012, Ballinger 2016, Caminsky 2016, Betti 2017, Yehia 2018). MLH1 Tyr379Cys was observed at an allele frequency of 0.015% (5/34,416) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may result in the creation of a cryptic splice donor site upstream of the natural splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MLH1 Tyr379Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MLH1: BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2017	Variant summary: The MLH1 c.1136A>G (p.Tyr379Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict the variant to create a cryptic splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5/121182 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant has been reported in patients with HNPCC, extra colonic cancer and epithelial ovarian cancer patients, however, without strong evidence for the causitive relationship between the variant and diseases. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This missense variant replaces tyrosine with cysteine at codon 379 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 23047549, 26898890), colorectal cancer (PMID: 14635101, 21404117), melanoma (25148578), sarcoma (PMID: 27498913), and mesothelioma (PMID: 28687356). This variant has also been reported in individuals whose phenotypes suggest that this variant is not likely to be pathogenic (ClinVar SCV004018102.1). This variant has been identified in 15/282670 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 22, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 13, 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	Aug 29, 2016	- -

Lynch syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces tyrosine with cysteine at codon 379 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 26898890), ovarian cancer (PMID: 23047549), colorectal cancer (PMID: 14635101, 21404117), melanoma (25148578), sarcoma (PMID: 27498913), and mesothelioma (PMID: 28687356). This variant has also been reported in individuals whose phenotypes suggest that this variant is not likely to be pathogenic (ClinVar variation ID: 142276). This variant has been identified in 15/282670 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. -
Likely benign, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Dec 19, 2018	Multifactorial likelihood analysis posterior probability < 0.05 (0.005) -

MLH1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2023

The MLH1 c.1136A>G variant is predicted to result in the amino acid substitution p.Tyr379Cys. This variant has been reported in individuals with colorectal and ovarian cancer, and an asbestos-exposed patient with malignant pleural mesothelioma; although no evidence was provided to determine its pathogenicity (Taylor et al. 2003. PubMed ID: 14635101; Pal et al. 2012. PubMed ID: 23047549; Betti ett al. 2017. PubMed ID: 28687356). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and is interpreted as likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142276/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;.;.;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.64

D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.6

D;D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.019

D;D;D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D;D;D

Polyphen

0.97

D;.;.;.;.;.

Vest4

0.48

MVP

0.83

MPC

0.33

ClinPred

0.75

GERP RS

2.6

Varity_R

0.26

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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