2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Position:

• chr2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant summary

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

The NM_000251.3(MSH2):​c.942+26_942+29delAAAA variant causes a intron change. The variant allele was found at a frequency of 0.0838 in 1,004,160 control chromosomes in the GnomAD database, including 56 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 0)
  • Exomes 𝑓: 0.089 (53 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• 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]

MSH2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-47414420-TAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 336428.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr2-47414420-TAAAA-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+26_942+29delAAAA		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+26_942+29delAAAA		intron_variant		1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 442 AN: 62230 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00170

Gnomad EAS AF: 0.000612

Gnomad SAS AF: 0.00451

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00514

GnomAD3 exomes AF: 0.0847 AC: 4442 AN: 52420 Hom.: 0 AF XY: 0.0830 AC XY: 2331 AN XY: 28096

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0841

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0889 AC: 83751 AN: 941928 Hom.: 53 AF XY: 0.0903 AC XY: 42096 AN XY: 466340

Gnomad4 AFR exome AF: 0.0906

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.0945

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0861

Gnomad4 OTH exome AF: 0.0943

GnomAD4 genome AF: 0.00709 AC: 441 AN: 62232 Hom.: 3 Cov.: 0 AF XY: 0.00714 AC XY: 197 AN XY: 27576

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00217

Gnomad4 ASJ AF: 0.00170

Gnomad4 EAS AF: 0.000612

Gnomad4 SAS AF: 0.00453

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00513

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Lynch syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 10, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

- -

Breast carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

This variant was identified as compound heterozygous. -

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;