3-37047531-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BS1_Supporting

The NM_000249.4(MLH1):c.1744C>G(p.Leu582Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L582F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 4.88

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 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37047531-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000267 (39/1461846) while in subpopulation EAS AF= 0.000983 (39/39694). AF 95% confidence interval is 0.000738. There are 0 homozygotes in gnomad4_exome. There are 22 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1744C>G	p.Leu582Val	missense_variant	Exon 16 of 19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.1744C>G	p.Leu582Val	missense_variant	Exon 16 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000983

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

AF:

0.0000131

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L582V variant (also known as c.1744C>G), located in coding exon 16 of the MLH1 gene, results from a C to G substitution at nucleotide position 1744. The leucine at codon 582 is replaced by valine, an amino acid with highly similar properties. This variant was identified in an individual meeting Amsterdam II criteria and the mismatch repair (MMR) activity for the variant was either gone or reduced in a functional assay using yeast (Shimodaira H et al. Nat. Genet. 1998 Aug;19(4):384-9). However, several studies have demonstrated expression levels, PMS2 binding, and MMR activity were similar to that of wild type MLH1 (Guerrette S et al., J. Biol. Chem. 1999 Mar; 274(10):6336-41; Kondo E et al., Cancer Res. 2003 Jun; 63(12):3302-8;Takahashi M et al., Cancer Res. 2007 May; 67(10):4595-604; Vo AT et al., EMBO Rep. 2005 May; 6(5):438-44). This variant has been identified in 45/12503 unselected Japanese colorectal cancer patients and in 102/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Sep 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 582 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). Functional studies have shown that this variant retained 93% of wild type MLH1 mismatch repair activity via yeast-2-hybrid and mismatch repair activity assays (PMID: 17510385, 15864295, 12810663, 10037723, 9697702, 21064154). Other functional studies reported altered protein interaction with mismatch repair machinery and loss of dominant mutator effect via yeast-2-hybrid and dominant mutator assays (PMID: 9697702, 15864295). This variant has been reported in individuals affected with Lynch syndrome, colorectal cancer, gastric cancer and mesothelioma (PMID: 7757073, 9697702, 17510385, 29050249, 29192238, 32206572, 33309985). This variant has been identified in 1/246040 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been observed in over one hundred individuals from a healthy control population (PMID: 33309985). 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

Dec 11, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MLH1 c.1744C>G (p.Leu582Val) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251262 control chromosomes (gnomAD) but was reported at a frequency of 0.001409 from 108604 chromosomes in ToMMo 54KJPN (jMorp variation ID0191aa67588b00000). c.1744C>G has been reported in the literature in at-least one family with Lynch Syndrome (Han_1995), individuals affected with various types of cancer (example: Kiyozumi_2019, Fuijita_2022,Okawa_2023) as well as in individuals from control study cohorts (example: Fuijita_2022, and Okawa_2023). Several publications report experimental evidence evaluating an impact on protein function. These results reproducibly reported no damaging effect of this variant on measures of interaction with PMS2, in-vitro MMR activity, and interaction with hMRE11 (Guerrette_1999, Takahashi_2007, Vo_2005, Kondo_2003). The following publications have been ascertained in the context of this evaluation (PMID: 10037723, 7757073, 12810663, 17510385, 15864295, 31386297, 26332594, 33309985, 36243179). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome

Uncertain:1

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 582 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A different variant affecting the same codon, c.1745T>C (p.Leu582Pro), is considered to be disease-causing (ClinVar variation ID: 89871), suggesting that leucine or similar amino acid at this position is important for the protein function. Functional studies have reported this variant to be normal to partially abnormal in mismatch repair and associated activities (PMID: 9697702, 17510385). Similarly, there was reported reduced PMS2 binding by co-immunoprecipitation (PMID: 20978114) but near wild-type PMS2 binding by yeast two-hybrid and GST pull down assays (PMID: 12810663, 15864295, 10037723). This variant has been reported in at least two families affected with Lynch syndrome associated cancer and the variant is reported to segregate with disease (PMID: 7757073, 9697702, 17510385, InSiGHT database). This variant has been identified in 1/246040 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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 582 of the MLH1 protein (p.Leu582Val). This variant is present in population databases (rs63751713, gnomAD 0.006%). This missense change has been observed in individual(s) with cancer and hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 7757073, 29050249, 31386297, 36896836). ClinVar contains an entry for this variant (Variation ID: 89869). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 9697702, 10037723, 12810663, 15864295, 17510385). 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:1

Jan 22, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 27363726]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;.;.;.;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.60

D;D;D;D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.085

T;T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T;T

Polyphen

0.26

B;.;.;.;.;.

Vest4

0.82

MVP

0.98

MPC

0.078

ClinPred

0.54

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

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.

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