chr2-47414420-TAAAAAAAAAAAAA-T

Position:

• chr2-47414420-TAAAAAAAAAAAAA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.942+17_942+29del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00439 in 1,044,430 control chromosomes in the GnomAD database, including 107 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (101 hom., cov: 0)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: MSH2 NM_000251.3 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• 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 -16 ACMG points.

• BP6: Variant 2-47414420-TAAAAAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAAAAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 182601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47414420-TAAAAAAAAAAAAA-T is described in Lovd as [Benign]. Variant chr2-47414420-TAAAAAAAAAAAAA-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+17_942+29del		splice_donor_5th_base_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+17_942+29del		splice_donor_5th_base_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.0398 AC: 2482 AN: 62390 Hom.: 100 Cov.: 0

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000311

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0124 AC: 648 AN: 52420 Hom.: 14 AF XY: 0.00933 AC XY: 262 AN XY: 28096

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.00595

Gnomad ASJ exome AF: 0.000801

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00156

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000639

Gnomad OTH exome AF: 0.00335

GnomAD4 exome AF: 0.00214 AC: 2102 AN: 982034 Hom.: 6 AF XY: 0.00187 AC XY: 915 AN XY: 488080

Gnomad4 AFR exome AF: 0.0805

Gnomad4 AMR exome AF: 0.00455

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0000423

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.000140

Gnomad4 NFE exome AF: 0.0000676

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.0398 AC: 2485 AN: 62396 Hom.: 101 Cov.: 0 AF XY: 0.0424 AC XY: 1173 AN XY: 27654

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000311

Gnomad4 OTH AF: 0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2014	The variant is found in HEREDICANCER,COLYNCH-HEREDIC panel(s). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2017	This alteration is classified as 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 specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 14, 2016	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 01, 2022

- -

Lynch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 24, 2015

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;