rs193922366

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.*35_*37delCTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,606,042 control chromosomes in the GnomAD database, including 334 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.022 ( 45 hom., cov: 32)

Exomes 𝑓: 0.018 ( 289 hom. )

Consequence

MLH1
NM_000249.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:10O:1

Conservation

PhyloP100: 0.0580

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 3-37050682-GTTC-G is Benign according to our data. Variant chr3-37050682-GTTC-G is described in ClinVar as [Benign]. Clinvar id is 36549.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050682-GTTC-G is described in Lovd as [Likely_benign]. Variant chr3-37050682-GTTC-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.022 (3345/152290) while in subpopulation AFR AF= 0.0308 (1280/41546). AF 95% confidence interval is 0.0294. There are 45 homozygotes in gnomad4. There are 1629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.35_37delCTT		3_prime_UTR_variant	Exon 19 of 19	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.35_37delCTT		3_prime_UTR_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3334

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0249

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.0248

GnomAD3 exomes

AF:

0.0168

AC:

4205

AN:

250506

Hom.:

AF XY:

0.0164

AC XY:

2221

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00963

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00591

Gnomad FIN exome

AF:

0.0264

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0165

GnomAD4 exome

AF:

0.0176

AC:

25584

AN:

1453752

Hom.:

289

AF XY:

0.0175

AC XY:

12660

AN XY:

723738

show subpopulations

Gnomad4 AFR exome

AF:

0.0300

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00606

Gnomad4 FIN exome

AF:

0.0260

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0171

GnomAD4 genome

AF:

0.0220

AC:

3345

AN:

152290

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1629

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0308

Gnomad4 AMR

AF:

0.0192

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0249

Gnomad4 NFE

AF:

0.0198

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0227

Hom.:

Bravo

AF:

0.0227

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Lynch syndrome

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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