chr2-47414420-TAA-T

Position:

• chr2-47414420-TAA-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000251.3(MSH2):​c.942+28_942+29del variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.179 in 965,430 control chromosomes in the GnomAD database, including 1,339 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (371 hom., cov: 0)
  • Exomes 𝑓: 0.18 (1339 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_donor_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 6.75

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-47414420-TAA-T is Benign according to our data. Variant chr2-47414420-TAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336427.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=2}. Variant chr2-47414420-TAA-T is described in Lovd as [Benign]. Variant chr2-47414420-TAA-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+28_942+29del		splice_donor_region_variant, intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.942+28_942+29del		splice_donor_region_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9816 AN: 62568 Hom.: 372 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.265

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.0914 AC: 4790 AN: 52420 Hom.: 14 AF XY: 0.0872 AC XY: 2450 AN XY: 28096

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.0818

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0841

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.179 AC: 173109 AN: 965430 Hom.: 1339 AF XY: 0.176 AC XY: 84578 AN XY: 479320

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.157 AC: 9812 AN: 62570 Hom.: 371 Cov.: 0 AF XY: 0.160 AC XY: 4436 AN XY: 27718

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Lynch syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Lynch syndrome 1 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

MSH2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 06, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 22, 2020

- -

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: rs11309117; hg19: chr2-47641559;