rs63750453

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000249.4(MLH1):c.304G>A(p.Glu102Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

Splicing: ADA: 0.9698

Clinical Significance

Likely pathogenic reviewed by expert panel P:10U:1

Conservation

PhyloP100: 9.42

Publications

13 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: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000249.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-37001052-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486866.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 3-37001051-G-A is Pathogenic according to our data. Variant chr3-37001051-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 90141.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.304G>A	p.Glu102Lys	missense_variant, splice_region_variant	Exon 3 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.304G>A	p.Glu102Lys	missense_variant, splice_region_variant	Exon 3 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1433492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714898

African (AFR)

AF:

0.00

AC:

AN:

32846

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.00

AC:

AN:

85656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086290

Other (OTH)

AF:

0.00

AC:

AN:

59504

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:2

Jul 12, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12183410, 16341550]. -

Sep 26, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 15, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/251334 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Results on protein functions were inconclusive. -

Feb 20, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies support a damaging effect: most show reduced mismatch repair activity and decreased expression levels (PMID: 11555625, 17510385, 23403630); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 12183410, 18383312, 21642682); 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; This variant is associated with the following publications: (PMID: 22736432, 18383312, 16395668, 23403630, 11555625, 21642682, 25525159, 16995940, 17510385, 26096739, 23554159, 23741719, 11781295, 14526391, 31857677, 33303966, 22753075, 16083711, 21120944, 11948175, 16341550, 18373977, 34326862, 12183410) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Aug 09, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E102K variant (also known as c.304G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an HNPCC family which met Amsterdam criteria and in vitro studies have found that the c.304G>A nucleotide substitution results in a 5-bp deletion in the 3' end of exon 3 (Nakagawa H et al. Cancer Res. 2002 Aug 15;62(16):4579-82). Additionally, further functional studies have shown decreased or complete loss of MMR function (Ellison AR. et al. Hum. Mol. Genet. 2001:1889-900; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). However, Takahashi et al. also studied the MMR activity of this variant in vitro and found this variant to result in an MMR function of 44.4% compared to 79.7% in WT which they report as inconclusive (Takahashi M et al. Cancer Research. 2007: 4595-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Carcinoma of colon

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Note: This variant was identified by this lab in a Teresa Minella. IHC not interpretable and MSI results were high. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Feb 15, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MLH1 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The presence of a cryptic 5' donor site 5 bp upstream of the canonical splice site was however noted at exon 3. Nakagawa et al (2002) suggest that this cryptic splice site is preferentially/exclusively used when the variant is present, resulting in a deletion of the last 5 bp of exon 3, eventually causing a downstream frameshift. A different study however, was unable to detect such an effect and reported no aberrant splicing in relation to the variant (Auclair_2006). Additional functional studies show defective or partially defective MMR activity (Ellison_2001; Hinrichsen_2013; Takahashi_2007, Reyes_2020). The variant was absent in 251344 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Duraturo_2015, Nakagawa_2002). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=5, including one expert panel- International Society for Gastrointestinal Hereditary Tumours (InSiGHT)). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Lynch syndrome 1

Pathogenic:1

Jun 13, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Multifactorial likelihood analysis posterior probability > 0.99 (0.995) -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Oct 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 11555625, 17510385, 18373977, 23403630). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). ClinVar contains an entry for this variant (Variation ID: 90141). This missense change has been observed in individuals with Lynch syndrome (PMID: 12183410, 21642682, 22736432, 23729658, 28514183, 31857677). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 102 of the MLH1 protein (p.Glu102Lys). -

not specified

Uncertain:1

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

PhyloP100

9.4

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.91

Gain of ubiquitination at E102 (P = 0.0408);

MVP

0.99

MPC

0.43

ClinPred

1.0

GERP RS

5.9

Varity_R

0.98

gMVP

0.98

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.85

Splicevardb

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over