rs41562513

chr3-37028946-G-Achr3-37028946-G-Cchr3-37028946-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000249.4(MLH1):c.1558+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,872 control chromosomes in the GnomAD database, including 1,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.053 (289 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1151 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:21
• Conservation: PhyloP100: -0.851

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-37028946-G-A is Benign according to our data. Variant chr3-37028946-G-A is described in ClinVar as [Benign]. Clinvar id is 36541.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37028946-G-A is described in Lovd as [Benign]. Variant chr3-37028946-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1558+14G>A		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1558+14G>A		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8104 AN: 152074 Hom.: 287 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0392

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0366 AC: 9200 AN: 251280 Hom.: 227 AF XY: 0.0355 AC XY: 4818 AN XY: 135790

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0215

Gnomad SAS exome AF: 0.0199

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0368 AC: 53820 AN: 1461678 Hom.: 1151 Cov.: 32 AF XY: 0.0361 AC XY: 26230 AN XY: 727156

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0378

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0534 AC: 8131 AN: 152194 Hom.: 289 Cov.: 32 AF XY: 0.0529 AC XY: 3932 AN XY: 74380

Gnomad4 AFR AF: 0.0993

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0392

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0402 Hom.: 55

Bravo AF: 0.0556

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:21

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
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. -

Lynch syndrome Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28932927, 27629256, 27884173, 15996210, 24689082, 23588873, 16395668) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 26, 2014	- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.1558+14G>A variant has been identified in 10 out of 670 proband chromosomes (frequency 0.015) in individuals with colorectal and breast cancer as well as the transitional cell carcinoma of the urinary tract; however no normal population controls were included in these studies (Furihata 2001, Kurzawski 2002, Murata 2002, Palicio 2002, Ward 2002, Lee 2005). It is listed in dbSNP database presented “With non-pathogenic allele” (ID#: rs41562513) with a “global minor allele frequency of 0.054 (1000 genomes), therefore increasing the likelihood that this variant is benign. One study demonstrated by RT-PCR that this variant did not affect splicing (Auclari_2006_16395668), increasing the likelihood this variant does not have clinical significance. This variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions, or positions +3 to +6 that are part of the splicing consensus sequence which sometimes affect splicing. In addition, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, based on the above information, this variant is classified as benign -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.20
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs41562513; hg19: chr3-37070437; COSMIC: COSV51618587; COSMIC: COSV51618587;