Variant chr3-36993455-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000413740.2(MLH1):c.-93G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,283,016 control chromosomes in the GnomAD database, including 42,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.23 ( 4663 hom., cov: 33)

Exomes 𝑓: 0.25 ( 38212 hom. )

Consequence

MLH1
ENST00000413740.2 5_prime_UTR

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11

Conservation

PhyloP100: -0.737

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

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 3-36993455-G-A is Benign according to our data. Variant chr3-36993455-G-A is described in ClinVar as [Benign]. Clinvar id is 89600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993455-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	XM_047448155.1 linkuse as main transcript			upstream_gene_variant			XP_047304111.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	UniProt
MLH1	ENST00000413740.2 linkuse as main transcript	c.-93G>A	5_prime_UTR_variant	1/15	1	ENSP00000416476
MLH1	ENST00000536378.5 linkuse as main transcript	c.-725G>A	5_prime_UTR_variant	1/18	2	ENSP00000444286	P40692-2
MLH1	ENST00000673673.2 linkuse as main transcript	c.-93G>A	5_prime_UTR_variant	1/18		ENSP00000500979

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35278

AN:

152130

Hom.:

4667

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.260

GnomAD4 exome

AF:

0.246

AC:

278381

AN:

1130768

Hom.:

38212

Cov.:

AF XY:

0.251

AC XY:

144931

AN XY:

577786

show subpopulations

Gnomad4 AFR exome

AF:

0.168

Gnomad4 AMR exome

AF:

0.329

Gnomad4 ASJ exome

AF:

0.330

Gnomad4 EAS exome

AF:

0.545

Gnomad4 SAS exome

AF:

0.374

Gnomad4 FIN exome

AF:

0.253

Gnomad4 NFE exome

AF:

0.213

Gnomad4 OTH exome

AF:

0.266

GnomAD4 genome

AF:

0.232

AC:

35286

AN:

152248

Hom.:

4663

Cov.:

AF XY:

0.238

AC XY:

17732

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.172

Gnomad4 AMR

AF:

0.274

Gnomad4 ASJ

AF:

0.328

Gnomad4 EAS

AF:

0.554

Gnomad4 SAS

AF:

0.383

Gnomad4 FIN

AF:

0.247

Gnomad4 NFE

AF:

0.215

Gnomad4 OTH

AF:

0.262

Alfa

AF:

0.235

Hom.:

8641

Bravo

AF:

0.234

Asia WGS

AF:

0.445

AC:

1546

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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+	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Feb 15, 2007	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27895767, 31530880, 24325908, 25804231, 25421847, 30093976, 22878509, 28195176, 26275295, 15382050, 22371642, 23226285, 24205329, 21206982, 21348638, 24689082, 17374836, 19956916, 18712731, 18405947, 18523027, 23374646, 20060799, 21565826, 23621208, 20860725) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 02, 2022

- -

Lynch syndrome

Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.6

DANN

Benign

0.77

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