3-37050682-GTTC-G

Position:

chr3-37050682-GTTC-G

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:

MLH1 (HGNC:):

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/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.35_37delCTT		3_prime_UTR_variant	19/19	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.35_37delCTT		3_prime_UTR_variant	19/19	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

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided

Uncertain:1Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Lynch syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

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