3-37025629-T-TTTTTTTA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000249.4(MLH1):c.1039-8_1039-7insTTTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.0980

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 3-37025629-T-TTTTTTTA is Benign according to our data. Variant chr3-37025629-T-TTTTTTTA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215447.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MLH1	NM_000249.4	MANE Select	c.1039-8_1039-7insTTTTTTA	splice_region intron	N/A	NP_000240.1
MLH1	NM_001354628.2		c.1039-8_1039-7insTTTTTTA	splice_region intron	N/A	NP_001341557.1
MLH1	NM_001354629.2		c.940-8_940-7insTTTTTTA	splice_region intron	N/A	NP_001341558.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1039-8_1039-7insTTTTTTA	splice_region intron	N/A	ENSP00000231790.3
MLH1	ENST00000456676.7	TSL:1	c.1039-8_1039-7insTTTTTTA	splice_region intron	N/A	ENSP00000416687.3
MLH1	ENST00000413740.2	TSL:1	c.1039-8_1039-7insTTTTTTA	splice_region intron	N/A	ENSP00000416476.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

135298

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

AF:

0.0000263

AC:

AN:

1103206

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

545202

show subpopulations

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

African (AFR)

AF:

0.000142

AC:

AN:

21110

American (AMR)

AF:

0.00

AC:

AN:

17426

Ashkenazi Jewish (ASJ)

AF:

0.0000569

AC:

AN:

17586

East Asian (EAS)

AF:

0.00

AC:

AN:

29082

South Asian (SAS)

AF:

0.00

AC:

AN:

38366

European-Finnish (FIN)

AF:

0.0000271

AC:

AN:

36842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3210

European-Non Finnish (NFE)

AF:

0.0000257

AC:

AN:

895810

Other (OTH)

AF:

0.0000228

AC:

AN:

43774

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000133157), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

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

AF:

0.00

AC:

AN:

135288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65430

African (AFR)

AF:

0.00

AC:

AN:

33996

American (AMR)

AF:

0.00

AC:

AN:

13736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3320

East Asian (EAS)

AF:

0.00

AC:

AN:

4932

South Asian (SAS)

AF:

0.00

AC:

AN:

4464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63904

Other (OTH)

AF:

0.00

AC:

AN:

1826

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MLH1: PM2, BP4

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.098

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over