rs2241031

chr3-37048783-C-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.1990-121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 979,796 control chromosomes in the GnomAD database, including 86,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12934 hom., cov: 32)
  • Exomes 𝑓: 0.41 (73452 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -3.24

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=-0.91).
• BP6: Variant 3-37048783-C-T is Benign according to our data. Variant chr3-37048783-C-T is described in ClinVar as [Benign]. Clinvar id is 89983.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048783-C-T 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.1990-121C>T		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1990-121C>T		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61231 AN: 151906 Hom.: 12928 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.410 AC: 339731 AN: 827772 Hom.: 73452 Cov.: 11 AF XY: 0.404 AC XY: 174886 AN XY: 432664

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.373

Gnomad4 ASJ exome AF: 0.416

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.369

Gnomad4 NFE exome AF: 0.458

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.403 AC: 61252 AN: 152024 Hom.: 12934 Cov.: 32 AF XY: 0.395 AC XY: 29361 AN XY: 74288

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.0782

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.388

Alfa AF: 0.432 Hom.: 8513

Bravo AF: 0.404

Asia WGS AF: 0.197 AC: 690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

-

- -

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

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.011
Dann	Benign	0.68

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: rs2241031; hg19: chr3-37090274;