3-37025638-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP3PP5_Moderate

The NM_000249.4(MLH1):c.1040C>T(p.Thr347Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. T347N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

Splicing: ADA: 0.9772

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.23

Publications

0 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 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 35 uncertain in NM_000249.4

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 3-37025638-C-T is Pathogenic according to our data. Variant chr3-37025638-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2691728.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1040C>T	p.Thr347Ile	missense_variant, splice_region_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
MLH1	ENST00000231790.8 link	c.1040C>T	p.Thr347Ile	missense_variant, splice_region_variant	Exon 12 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116430

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000356

AC:

AN:

843292

Hom.:

Cov.:

AF XY:

0.00000472

AC XY:

AN XY:

423828

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16600

American (AMR)

AF:

0.0000391

AC:

AN:

25576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15508

East Asian (EAS)

AF:

0.0000480

AC:

AN:

20848

South Asian (SAS)

AF:

0.00

AC:

AN:

37414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3160

European-Non Finnish (NFE)

AF:

0.00000153

AC:

AN:

652130

Other (OTH)

AF:

0.00

AC:

AN:

33336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

116430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

53862

African (AFR)

AF:

0.00

AC:

AN:

28806

American (AMR)

AF:

0.00

AC:

AN:

9420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3218

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

3630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60710

Other (OTH)

AF:

0.00

AC:

AN:

1480

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:1

Feb 02, 2024

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The patient, who is heterozygous for the variant, has had breast cancer and melanoma. Her father also has melanoma. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;.;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;.;.;.;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Benign

0.038

D;D;D;D;D;D

Sift4G

Benign

0.28

T;D;D;D;D;T

Polyphen

0.38

B;.;.;.;.;.

Vest4

0.71

MutPred

0.41

Loss of phosphorylation at T347 (P = 0.0266);.;.;.;.;.;

MVP

0.96

MPC

0.089

ClinPred

0.97

GERP RS

5.7

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.21

gMVP

0.48

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.79

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

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over