rs4647255

Positions:

• chr3-37008763-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.454-51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,491,372 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.031 (93 hom., cov: 32)
  • Exomes 𝑓: 0.026 (535 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.135

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-37008763-T-C is Benign according to our data. Variant chr3-37008763-T-C is described in ClinVar as [Benign]. Clinvar id is 90236.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37008763-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0311 (4737/152344) while in subpopulation AFR AF= 0.0431 (1791/41568). AF 95% confidence interval is 0.0414. There are 93 homozygotes in gnomad4. There are 2277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 93 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.454-51T>C		intron_variant		ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.454-51T>C		intron_variant		1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4717 AN: 152226 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0237 AC: 5869 AN: 247824 Hom.: 96 AF XY: 0.0232 AC XY: 3114 AN XY: 134458

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00941

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0257 AC: 34400 AN: 1339028 Hom.: 535 Cov.: 20 AF XY: 0.0254 AC XY: 17085 AN XY: 672862

Gnomad4 AFR exome AF: 0.0411

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000768

Gnomad4 SAS exome AF: 0.00965

Gnomad4 FIN exome AF: 0.0374

Gnomad4 NFE exome AF: 0.0275

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0311 AC: 4737 AN: 152344 Hom.: 93 Cov.: 32 AF XY: 0.0306 AC XY: 2277 AN XY: 74508

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0358

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0301 Hom.: 31

Bravo AF: 0.0311

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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% -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Jan 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4647255; hg19: chr3-37050254; COSMIC: COSV51623525; COSMIC: COSV51623525;