Genetic Variant NM_000249.4:c.1039-10_1039-8dupTTT (chr3-37025608-A-ATTT) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.00158

AC:

AN:

13956

Hom.:

AF XY:

0.00119

AC XY:

AN XY:

8400

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 SAS exome

AF:

0.00325

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

Gnomad4 AFR exome

AF:

0.00420

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00192

Gnomad4 EAS exome

AF:

0.00264

Gnomad4 SAS exome

AF:

0.00322

Gnomad4 FIN exome

AF:

0.00328

Gnomad4 NFE exome

AF:

0.000860

Gnomad4 OTH exome

AF:

0.00115

GnomAD4 genome

AF:

0.00184

AC:

AN:

48272

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

21492

show subpopulations

Gnomad4 AFR

AF:

0.00474

Gnomad4 AMR

AF:

0.00184

Gnomad4 ASJ

AF:

0.00263

Gnomad4 EAS

AF:

0.00484

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000267

Gnomad4 OTH

AF:

0.00660

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

Feb 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

La Branchor

0.24

BranchPoint Hunter

2.0

Splicing

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