3-37025608-ATTTTTTTTT-ATTTTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000249.4(MLH1):c.1039-12_1039-8dupTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0340

Publications

1 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: ClinGen, Orphanet, G2P
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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, 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 -2 ACMG points.

BP6

Variant 3-37025608-A-ATTTTT is Benign according to our data. Variant chr3-37025608-A-ATTTTT is described in ClinVar as Benign. ClinVar VariationId is 2575409.Status of the report is criteria_provided_single_submitter, 1 stars.

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	UniProt
MLH1	NM_000249.4	MANE Select	c.1039-12_1039-8dupTTTTT	splice_region intron	N/A	NP_000240.1	P40692-1
MLH1	NM_001354628.2		c.1039-12_1039-8dupTTTTT	splice_region intron	N/A	NP_001341557.1	A0A087WX20
MLH1	NM_001354629.2		c.940-12_940-8dupTTTTT	splice_region intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1039-29_1039-28insTTTTT	intron	N/A	ENSP00000231790.3	P40692-1
MLH1	ENST00000456676.7	TSL:1	c.1039-29_1039-28insTTTTT	intron	N/A	ENSP00000416687.3	H0Y818
MLH1	ENST00000413740.2	TSL:1	c.1039-29_1039-28insTTTTT	intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes

AF:

0.000166

AC:

AN:

48290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

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:

0.000182

AC:

AN:

258420

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

128304

show subpopulations

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

African (AFR)

AF:

0.000299

AC:

AN:

3342

American (AMR)

AF:

0.00314

AC:

AN:

1274

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

2090

East Asian (EAS)

AF:

0.000657

AC:

AN:

3042

South Asian (SAS)

AF:

0.000755

AC:

AN:

5298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

526

European-Non Finnish (NFE)

AF:

0.000125

AC:

AN:

232898

Other (OTH)

AF:

0.000573

AC:

AN:

8728

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000928146), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.349

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:

0.000166

AC:

AN:

48278

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

AN XY:

21494

show subpopulations

African (AFR)

AF:

0.000498

AC:

AN:

12042

American (AMR)

AF:

0.00

AC:

AN:

3256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1520

East Asian (EAS)

AF:

0.000969

AC:

AN:

2064

South Asian (SAS)

AF:

0.00

AC:

AN:

1336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

26192

Other (OTH)

AF:

0.00

AC:

AN:

606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.034

La Branchor

0.24

BranchPoint Hunter

2.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over