rs63750430

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM5PP3_ModerateBP6

The NM_000249.4(MLH1):​c.1154G>A​(p.Arg385His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R385C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:3

Conservation

PhyloP100: 9.13
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37025751-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871
BP6
Variant 3-37025752-G-A is Benign according to our data. Variant chr3-37025752-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 140759.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Benign=2, Likely_benign=1}. Variant chr3-37025752-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.1154G>A p.Arg385His missense_variant Exon 12 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.1154G>A p.Arg385His missense_variant Exon 12 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.0000396
AC:
6
AN:
151648
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000243
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000589
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251414
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135872
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:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461878
Hom.:
1
Cov.:
34
AF XY:
0.0000413
AC XY:
30
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000396
AC:
6
AN:
151648
Hom.:
0
Cov.:
31
AF XY:
0.0000405
AC XY:
3
AN XY:
74034
show subpopulations
Gnomad4 AFR
AF:
0.0000243
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:13Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:5Benign:1
Mar 26, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 10, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 16, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MLH1 c.1154G>A (p.Arg385His) missense change has a maximum subpopulation frequency of 0.019% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in one individual with Lynch syndrome-related colorectal cancer (PMID: 35223509), as well as in individuals with prostate cancer (PMID: 31248605), lung adenocarcinoma (PMID: 35280419), and familial breast/ovarian cancer (PMID: 30982232). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nov 21, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

not provided Uncertain:3
Dec 28, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate MLH1 protein expression and mismatch repair (MMR) activity similar to wildtype (PMID: 37224528); Observed in individuals with colorectal, breast, or other cancers, as well as in unaffected controls is a study of biliary tract cancer (PMID: 36243179, 27498913, 30982232, 35223509, 35264596, 36627197, 35449176); This variant is associated with the following publications: (PMID: 31391288, 27149842, 33042626, 31248605, 36215471, 27498913, 35223509, 30982232, 35264596, 36627197, 37224528, Abudabbous2023[CaseReport], 36243179, 35449176) -

Jun 03, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MLH1 c.1154G>A (p.Arg385His) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 30982232 (2019), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1), 35264596 (2022), 35449176 (2022)), prostate cancer (PMID: 31248605 (2019)), colorectal cancer (PMID: 35223509 (2022)), gastric cancer (PMID: 36627197 (2023)), and another unspecified cancer (PMID: 31248605 (2020)). This variant is also found in reportedly healthy individuals (PMID: 32980694 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1), 36243179 (2022)). The frequency of this variant in the general population, 0.0002 (6/30616 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. -

May 10, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Sep 11, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 17, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 385 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 reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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
Nov 14, 2022
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.1154G>A (p.Arg385His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251414 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.1154G>A has been reported in the literature as a VUS in settings of multi-gene testing in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome, and in individuals affected with prostate and other cancers (e.g. Wang_2019, Wei_2019, Li_2021, Fanale_2022). These reports do not provide unequivocal conclusions about association of the variant with HNPCC/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=9) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1
Aug 23, 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 arginine with histidine at codon 385 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). A functional study demonstrated this variant has no impact on protein expression or mismatch repair activity, with similar activity to wild type protein (PMID: 37224528). This variant has been observed in an individual affected with colorectal cancer (PMID: 35223509), an individual affected with Ewing sarcoma (PMID: 27498913), and individual affected with gastric cancer who also had a pathogenic variant in the ATM gene (PMID: 36627197), and in two unaffected individuals in a pancreatic case-control study (PMID: 32980694). This variant has been identified in 15/282582 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. -

Lynch-like syndrome Uncertain:1
Jul 01, 2019
Constitutional Genetics Lab, Leon Berard Cancer Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D;.;.;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;.;.;.;D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D
MetaSVM
Uncertain
0.36
D
MutationAssessor
Pathogenic
3.0
M;.;.;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-4.3
D;D;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.68
MVP
0.96
MPC
0.45
ClinPred
0.85
D
GERP RS
5.7
Varity_R
0.65
gMVP
0.69

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.

Other links and lift over

dbSNP: rs63750430; hg19: chr3-37067243; COSMIC: COSV51623561; COSMIC: COSV51623561; API