rs9876116

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000231790.8(MLH1):c.1668-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,544,504 control chromosomes in the GnomAD database, including 137,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.41 ( 13269 hom., cov: 32)

Exomes 𝑓: 0.41 ( 123996 hom. )

Consequence

MLH1
ENST00000231790.8 intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:18

Conservation

PhyloP100: -0.274

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 -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 3-37042249-A-G is Benign according to our data. Variant chr3-37042249-A-G is described in ClinVar as [Benign]. Clinvar id is 36542.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37042249-A-G is described in Lovd as [Benign]. Variant chr3-37042249-A-G is described in Lovd as [Pathogenic]. Variant chr3-37042249-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1668-19A>G		intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1668-19A>G		intron_variant		1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.409

AC:

62105

AN:

151894

Hom.:

13263

Cov.:

show subpopulations

Gnomad AFR

AF:

0.411

Gnomad AMI

AF:

0.537

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.0778

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.358

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.451

Gnomad OTH

AF:

0.400

GnomAD3 exomes

AF:

0.371

AC:

92862

AN:

250418

Hom.:

18818

AF XY:

0.370

AC XY:

50116

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.413

Gnomad EAS exome

AF:

0.0588

Gnomad SAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.356

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.391

GnomAD4 exome

AF:

0.414

AC:

576566

AN:

1392492

Hom.:

123996

Cov.:

AF XY:

0.410

AC XY:

285671

AN XY:

696456

show subpopulations

Gnomad4 AFR exome

AF:

0.408

Gnomad4 AMR exome

AF:

0.369

Gnomad4 ASJ exome

AF:

0.412

Gnomad4 EAS exome

AF:

0.113

Gnomad4 SAS exome

AF:

0.255

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.444

Gnomad4 OTH exome

AF:

0.393

GnomAD4 genome

AF:

0.409

AC:

62124

AN:

152012

Hom.:

13269

Cov.:

AF XY:

0.401

AC XY:

29760

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.410

Gnomad4 AMR

AF:

0.413

Gnomad4 ASJ

AF:

0.404

Gnomad4 EAS

AF:

0.0778

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.358

Gnomad4 NFE

AF:

0.451

Gnomad4 OTH

AF:

0.395

Alfa

AF:

0.418

Hom.:

2915

Bravo

AF:

0.411

Asia WGS

AF:

0.197

AC:

690

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -

not provided

Uncertain:1Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Lynch syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.9

DANN

Benign

0.63

BranchPoint Hunter

1.0

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