chr3-37025608-A-ATTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.1039-10_1039-8dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0010 ( 5 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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: 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: Benign. The variant received -16 ACMG points.

BP6

Variant 3-37025608-A-ATTT is Benign according to our data. Variant chr3-37025608-A-ATTT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00184 (89/48272) while in subpopulation EAS AF = 0.00484 (10/2064). AF 95% confidence interval is 0.00375. There are 2 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1039-10_1039-8dupTTT		splice_region_variant, intron_variant	Intron 11 of 18	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.1039-29_1039-28insTTT		intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

AN:

48284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00474

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00263

Gnomad EAS

AF:

0.00481

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0208

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.00660

GnomAD2 exomes

AF:

0.00158

AC:

AN:

13956

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.00746

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.000773

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000598

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00101

AC:

260

AN:

257918

Hom.:

Cov.:

AF XY:

0.000937

AC XY:

120

AN XY:

128044

show subpopulations

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

African (AFR)

AF:

0.00420

AC:

AN:

3334

American (AMR)

AF:

0.00237

AC:

AN:

1268

Ashkenazi Jewish (ASJ)

AF:

0.00192

AC:

AN:

2084

East Asian (EAS)

AF:

0.00264

AC:

AN:

3026

South Asian (SAS)

AF:

0.00322

AC:

AN:

5284

European-Finnish (FIN)

AF:

0.00328

AC:

AN:

1218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

526

European-Non Finnish (NFE)

AF:

0.000860

AC:

200

AN:

232466

Other (OTH)

AF:

0.00115

AC:

AN:

8712

⚠️ 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: 0.324

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00184

AC:

AN:

48272

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

21492

show subpopulations

African (AFR)

AF:

0.00474

AC:

AN:

12038

American (AMR)

AF:

0.00184

AC:

AN:

3256

Ashkenazi Jewish (ASJ)

AF:

0.00263

AC:

AN:

1520

East Asian (EAS)

AF:

0.00484

AC:

AN:

2064

South Asian (SAS)

AF:

0.00

AC:

AN:

1336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

874

Middle Eastern (MID)

AF:

0.0227

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000267

AC:

AN:

26192

Other (OTH)

AF:

0.00660

AC:

AN:

606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 18, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Oct 28, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MLH1: BP4, BS2 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Apr 15, 2016

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over