2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAA

Position:

• chr2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant summary

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

The NM_000251.3(MSH2):​c.942+21_942+29del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000686 in 1,043,724 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_donor_5th_base, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-TAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1692300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00182 (113/62244) while in subpopulation AFR AF= 0.00511 (99/19380). AF 95% confidence interval is 0.00429. There are 2 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+21_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+21_942+29del		splice_donor_5th_base_variant, intron_variant		1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 113 AN: 62242 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00290

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000903

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000311

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000614 AC: 603 AN: 981480 Hom.: 0 AF XY: 0.000613 AC XY: 299 AN XY: 487784

Gnomad4 AFR exome AF: 0.00232

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00108

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.000470

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00182 AC: 113 AN: 62244 Hom.: 2 Cov.: 0 AF XY: 0.00196 AC XY: 54 AN XY: 27578

Gnomad4 AFR AF: 0.00511

Gnomad4 AMR AF: 0.00290

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000906

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000311

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 18, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 05, 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;