Genetic Variant NM_000249.4:c.1039-8delT (chr3-37025608-AT-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_000249.4(MLH1):c.1039-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0090 ( 1 hom. )

Consequence

MLH1
NM_000249.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0340

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 3-37025608-AT-A is Benign according to our data. Variant chr3-37025608-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 193978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00273 (132/48274) while in subpopulation AFR AF= 0.00615 (74/12042). AF 95% confidence interval is 0.00502. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.1039-8delT		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.1039-28delT		intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

132

AN:

48286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00607

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00154

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00529

Gnomad SAS

AF:

0.00447

Gnomad FIN

AF:

0.00228

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00331

GnomAD4 exome

AF:

0.00900

AC:

2314

AN:

257244

Hom.:

Cov.:

AF XY:

0.00856

AC XY:

1093

AN XY:

127696

show subpopulations

Gnomad4 AFR exome

AF:

0.00873

Gnomad4 AMR exome

AF:

0.0190

Gnomad4 ASJ exome

AF:

0.00482

Gnomad4 EAS exome

AF:

0.0192

Gnomad4 SAS exome

AF:

0.0242

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.00836

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.00273

AC:

132

AN:

48274

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

AN XY:

21490

show subpopulations

Gnomad4 AFR

AF:

0.00615

Gnomad4 AMR

AF:

0.00154

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00533

Gnomad4 SAS

AF:

0.00374

Gnomad4 FIN

AF:

0.00228

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00331

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

May 17, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 03, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

La Branchor

0.24

BranchPoint Hunter

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over