rs4234259

chr3-37007142-A-G

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.453+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,213,338 control chromosomes in the GnomAD database, including 112,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13128 hom., cov: 32)
  • Exomes 𝑓: 0.43 (99539 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.347

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=-0.92).
• BP6: Variant 3-37007142-A-G is Benign according to our data. Variant chr3-37007142-A-G is described in ClinVar as [Benign]. Clinvar id is 90227.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37007142-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.453+79A>G		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.453+79A>G		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61750 AN: 151922 Hom.: 13124 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.425 AC: 451544 AN: 1061298 Hom.: 99539 AF XY: 0.419 AC XY: 228559 AN XY: 545124

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.426

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.262

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.466

Gnomad4 OTH exome AF: 0.407

GnomAD4 genome AF: 0.406 AC: 61772 AN: 152040 Hom.: 13128 Cov.: 32 AF XY: 0.399 AC XY: 29618 AN XY: 74318

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.0777

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.388

Alfa AF: 0.422 Hom.: 2420

Bravo AF: 0.408

Asia WGS AF: 0.197 AC: 691 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.3
Dann	Benign	0.81

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: rs4234259; hg19: chr3-37048633;