chr2-47408384-C-CT

Position:

• chr2-47408384-C-CT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000251.3(MSH2):​c.212-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 143,858 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.21 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.95

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 -12 ACMG points.

• BP6: Variant 2-47408384-C-CT is Benign according to our data. Variant chr2-47408384-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 491795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0019 (273/143858) while in subpopulation SAS AF= 0.0117 (53/4518). AF 95% confidence interval is 0.00921. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.212-4dupT		splice_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.212-4dupT		splice_region_variant, intron_variant		1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 270 AN: 143802 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000534

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00140

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000401

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.00910

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00307

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.208 AC: 194346 AN: 932154 Hom.: 0 Cov.: 0 AF XY: 0.207 AC XY: 95722 AN XY: 462300

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.212

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.00190 AC: 273 AN: 143858 Hom.: 1 Cov.: 31 AF XY: 0.00202 AC XY: 141 AN XY: 69822

Gnomad4 AFR AF: 0.000558

Gnomad4 AMR AF: 0.00147

Gnomad4 ASJ AF: 0.000298

Gnomad4 EAS AF: 0.000402

Gnomad4 SAS AF: 0.0117

Gnomad4 FIN AF: 0.00910

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00305

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2015	- -

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 21, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

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: rs746333570; hg19: chr2-47635523;