rs200919928

Positions:

• chr3-37050682-GTTC-G
• chr3-37050682-G-GTTC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000249.4(MLH1):​c.*35_*37del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,606,042 control chromosomes in the GnomAD database, including 334 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.022 (45 hom., cov: 32)
  • Exomes 𝑓: 0.018 (289 hom.)
• Consequence: MLH1 NM_000249.4 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:10 O:1
• Conservation: PhyloP100: 0.0580

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 -16 ACMG points.

• BP6: Variant 3-37050682-GTTC-G is Benign according to our data. Variant chr3-37050682-GTTC-G is described in ClinVar as [Benign]. Clinvar id is 36549.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050682-GTTC-G is described in Lovd as [Likely_benign]. Variant chr3-37050682-GTTC-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.022 (3345/152290) while in subpopulation AFR AF= 0.0308 (1280/41546). AF 95% confidence interval is 0.0294. There are 45 homozygotes in gnomad4. There are 1629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.*35_*37del		3_prime_UTR_variant	19/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.*35_*37del		3_prime_UTR_variant	19/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3334 AN: 152172 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0168 AC: 4205 AN: 250506 Hom.: 50 AF XY: 0.0164 AC XY: 2221 AN XY: 135464

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00591

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0176 AC: 25584 AN: 1453752 Hom.: 289 AF XY: 0.0175 AC XY: 12660 AN XY: 723738

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00606

Gnomad4 FIN exome AF: 0.0260

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0220 AC: 3345 AN: 152290 Hom.: 45 Cov.: 32 AF XY: 0.0219 AC XY: 1629 AN XY: 74456

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0249

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0227 Hom.: 7

Bravo AF: 0.0227

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:4 Other:1

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2016	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Lynch syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
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;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Computational scores

Source: dbNSFP v4.3

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: rs193922366; hg19: chr3-37092173;