rs63751145

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000249.4(MLH1):c.1474G>A(p.Ala492Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,076 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. A492P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 5.96

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1474G>A	p.Ala492Thr	missense_variant	Exon 13 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.1474G>A	p.Ala492Thr	missense_variant	Exon 13 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152224

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251482

AF XY:

0.0000221

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000610

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Oct 15, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Dec 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A492T variant (also known as c.1474G>A), located in coding exon 13 of the MLH1 gene, results from a G to A substitution at nucleotide position 1474. The alanine at codon 492 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in at least one individual whose Lynch-related tumor demonstrated loss of MLH1/PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). This alteration was reported in an individual with sporadic, MSI-H rectal cancer diagnosed at age 41 years (Moslein G et al. Hum. Mol. Genet. 1996 Sep; 5(9):1245-52). This alteration has also been detected in conjunction with a pathogenic mutation in MSH6 in an individual with MSI-H and MSH6 absent colon cancer at age 39 years (Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). Several groups have performed functional studies on this alteration, mostly in yeast, primarily yielding inconsistent results relating to this alteration’s possible effect on protein function (Shimodaira H et al. Nat. Genet. 1998 Aug; 19(4):384-9; Kondo E et al. Cancer Res. 2003 Jun; 63(12):3302-8; Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604; Ou J et al. Hum. Mutat. 2007 Nov; 28(11):1047-54). 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. -

Jun 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with threonine at codon 492 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 reported this variant caused no significant impact on MLH function in an in vitro MMR assay (PMID: 17510385) or on binding to PMS2 and EXO1 (PMID: 12810663), and there have been conflicting results regarding the variant's impact on the dominant mutator effect in yeast (PMID: 9697702, 17510385). This variant has been reported in individuals affected with colorectal cancer (PMID: 8872463, 18301448, 21404117). One of these probands also carried a pathogenic variant in the MSH6 gene, which could explain the observed phenotype (PMID: 18301448). This variant has been identified in 6/282896 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. -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:2Benign:1

Nov 28, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Lynch syndrome 2 (MIM#609310), mismatch repair cancer syndrome 1 (MIM#276300), and Muir-Torre syndrome (MIM#158320). (I) 0108 - This gene is associated with both recessive and dominant disease. Lynch syndrome 2 (MIM#609310) and Muir-Torre syndrome (MIM#158320) are inherited in an autosomal dominant manner, while mismatch repair cancer syndrome 1 (MIM#276300) is autosomal recessive. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 (10 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Ala492Gly), p.(Ala492Pro), and p.(Ala492Val) have been classified as variants of uncertain significance by clinical laboratories in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical laboratories in ClinVar, and has been observed in at least one individual with colorectal cancer who had no family history and also had a nonsense variant in MSH6 (PMIDs: 8872463, 18301448). (I) 1004 - This variant has moderate functional evidence supporting normal protein function. This variant has been shown to have ~65% of wild type MMR activity, over 75% MLH1 expression, and was positive (had activity) in two of three yeast based MMR assays (PMID: 17510385). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 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]. -

not provided

Uncertain:2

Dec 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MLH1 c.1474G>A (p.Ala492Thr) variant has been reported in the published literature in individuals with breast cancer (PMID: 35884425 (2022)) and colorectal cancer (PMID: 8872463 (1996), 18301448 (2008)), as well as reportedly healthy individuals (PMID: 35884425 (2022)). One of the individuals with colorectal cancer had a co-occurring pathogenic MSH6 variant, which suggests that the MLH1 variant was not the primary cause of disease (PMID: 18301448 (2008)). Multiple functional studies have yielded conflicting results for this variant's effect on MMR activity, protein-protein interactions, and dominant mutator effect (PMID: 9697702 (1998), 12810663 (2003), 17510385 (2007), 18373977 (2008)). The frequency of this variant in the general population, 0.000039 (5/129194 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jul 09, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intact PMS2 & EXO1 binding, sufficient MMR repair activity, normal MLH1 expression and stability, and reduced dominant mutator effect (PMID: 9697702, 12810663, 17510385); Observed in several individuals with early onset colorectal cancer, one of whom also carried a pathogenic MSH6 variant (PMID: 8872463, 18301448, 23741719); This variant is associated with the following publications: (PMID: 18383312, 12810663, 17510385, 18301448, 17594722, 9697702, 8872463, 8895729, 15340264, 17074586, 16995940, 17192056, 11948175, 21404117, 18373977, 23741719, 30374176, 22290698, 22753075, 12799449, 20533529) -

Lynch syndrome

Uncertain:1Benign:1

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The MLH1 variant designated as NM_000249.3: c.1474G>A (p.Ala492Thr) is classified as likely benign. Pretest probability for pathogenicity was less than 0.1 based on computer prediction with PolyPhen2 of 0.033 and MAPP of 2.75 (Thompson et al. 2013, PMID:12900794). Family history analysis of one observed family revealed no Lynch syndrome-associated cancers in multiple individuals tested to have the variant. Cosegregation analysis of the same observed family was performed using analyze.myvariant.org (RaÃ±ola et al, 2018, PMID:28965303) and gives a likelihood ratio of 0.19 to 1 that this allele explains cancers in the family (Thompson et al. 2003, PMID:1290079), which provides evidence against pathogenicity. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MLH1 function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not specified

Uncertain:1

Nov 03, 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.1474G>A (p.Ala492Thr) results in a non-conservative amino acid change located in the region responsible for the interaction of MLH1 with PMS2 (aa 492-756) of the encoded protein sequence (Hardt_2011). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1474G>A has been reported in the literature in individuals affected with Lynch Syndrome, HNPCC and different types of cancer as well as in at least one healthy individual (Moslein_1996, Thibodeau_1996, Lucci-Cordisco_2006, Steinke_2008, Hardt_2011, Tsai_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one co-occurrence with another pathogenic variant has been reported (MSH6 c.467C>G, p.Ser156X), providing supporting evidence for a benign role (Steinke_2008). Functional studies report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Shimodaira_1998, Kondo_ 2003, Lucci-Cordisco_2006, Takahashi_2007, Zhao_2008). The following publications have been ascertained in the context of this evaluation (PMID: 9699680, 21404117, 12810663, 17192056, 8872463, 17594722, 9697702, 18301448, 17510385, 8895729, 30374176, 18373977). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as likely benign (n=1) and uncertain significance (n=5). 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

Aug 27, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 01, 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

Benign

0.14

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.;.;.;.;T;T

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T;.;.;.;T;T;T

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.72

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

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.7

L;.;.;.;.;.;.;.

PhyloP100

6.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.92

N;N;N;N;N;N;D;N

REVEL

Uncertain

0.50

Sift

Benign

0.065

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

Sift4G

Benign

0.50

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

Polyphen

0.033

B;.;.;.;.;.;.;.

Vest4

0.48

MutPred

0.72

Gain of glycosylation at T491 (P = 0.1026);.;.;.;.;.;.;.;

MVP

0.97

MPC

0.065

ClinPred

0.45

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.39

Mutation Taster

=3/97

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over