3-37020549-T-C

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.1038+86T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,466,636 control chromosomes in the GnomAD database, including 139,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13125 hom., cov: 32)
  • Exomes 𝑓: 0.43 (126151 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.0520

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=-0.94).
• BP6: Variant 3-37020549-T-C is Benign according to our data. Variant chr3-37020549-T-C is described in ClinVar as [Benign]. Clinvar id is 89615.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37020549-T-C 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.1038+86T>C		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1038+86T>C		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61759 AN: 151944 Hom.: 13121 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.391

GnomAD4 exome AF: 0.432 AC: 567769 AN: 1314574 Hom.: 126151 AF XY: 0.426 AC XY: 280228 AN XY: 657370

Gnomad4 AFR exome AF: 0.391

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.406 AC: 61781 AN: 152062 Hom.: 13125 Cov.: 32 AF XY: 0.398 AC XY: 29620 AN XY: 74330

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.0782

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.387

Alfa AF: 0.340 Hom.: 1254

Bravo AF: 0.408

Asia WGS AF: 0.197 AC: 689 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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	-0.94
Cadd	Benign	12
Dann	Benign	0.61

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: rs2286939; hg19: chr3-37062040; COSMIC: COSV99212310; COSMIC: COSV99212310;