rs17568951

Variant names:

• chr2-47580354-T-C
• rs17568951
• NM_001406631.1:c.2752+67934T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001406631.1(MSH2):​c.2752+67934T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 151,582 control chromosomes in the GnomAD database, including 2,846 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2846 hom., cov: 30)
• Consequence: MSH2 NM_001406631.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406631.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_001406631.1		c.2752+67934T>C		intron	N/A	NP_001393560.1
	MSH2	NM_001406632.1		c.2752+67934T>C		intron	N/A	NP_001393561.1
	MSH2	NM_001406633.1		c.2752+67934T>C		intron	N/A	NP_001393562.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000644092.1		n.*1053-27038T>C		intron	N/A	ENSP00000496351.1
	MSH2	ENST00000645339.1		n.2753-52448T>C		intron	N/A	ENSP00000496441.1
	MSH2	ENST00000646415.1		n.2753-27038T>C		intron	N/A	ENSP00000495543.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28074 AN: 151464 Hom.: 2847 Cov.: 30

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.185 AC: 28066 AN: 151582 Hom.: 2846 Cov.: 30 AF XY: 0.182 AC XY: 13485 AN XY: 74012

African (AFR) AF: 0.137 AC: 5642 AN: 41330

American (AMR) AF: 0.183 AC: 2776 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3468

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5176

South Asian (SAS) AF: 0.165 AC: 794 AN: 4802

European-Finnish (FIN) AF: 0.162 AC: 1692 AN: 10420

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15983 AN: 67890

Other (OTH) AF: 0.183 AC: 384 AN: 2100

Alfa AF: 0.197 Hom.: 2345

Bravo AF: 0.183

Asia WGS AF: 0.0800 AC: 280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.039
DANN	Benign	0.51
PhyloP100		-2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17568951; hg19: chr2-47807493;