2-47617366-A-G

Variant names:

• chr2-47617366-A-G
• rs6544997
• NM_001406631.1:c.2753-43607A>G

Variant summary

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

The NM_001406631.1(MSH2):​c.2753-43607A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,972 control chromosomes in the GnomAD database, including 26,261 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 0.58 (26261 hom., cov: 31)
• Consequence: MSH2 NM_001406631.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.701
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_001406631.1	c.2753-43607A>G		intron_variant	Intron 16 of 17		NP_001393560.1
MSH2	NM_001406632.1	c.2753-39834A>G		intron_variant	Intron 16 of 18		NP_001393561.1
MSH2	NM_001406633.1	c.2753-43607A>G		intron_variant	Intron 16 of 18		NP_001393562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000644092.1	n.*1242+9785A>G		intron_variant	Intron 17 of 19			ENSP00000496351.1
MSH2	ENST00000645339.1	n.2753-15436A>G		intron_variant	Intron 16 of 18			ENSP00000496441.1
MSH2	ENST00000646415.1	n.*125+9785A>G		intron_variant	Intron 17 of 17			ENSP00000495543.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87619 AN: 151854 Hom.: 26224 Cov.: 31

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.553

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

GnomAD4 genome AF: 0.577 AC: 87697 AN: 151972 Hom.: 26261 Cov.: 31 AF XY: 0.576 AC XY: 42789 AN XY: 74266

African (AFR) AF: 0.739 AC: 30589 AN: 41414

American (AMR) AF: 0.563 AC: 8596 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2045 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1956 AN: 5156

South Asian (SAS) AF: 0.525 AC: 2534 AN: 4824

European-Finnish (FIN) AF: 0.553 AC: 5839 AN: 10552

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.507 AC: 34471 AN: 67968

Other (OTH) AF: 0.548 AC: 1155 AN: 2108

Alfa AF: 0.525 Hom.: 90144

Bravo AF: 0.585

Asia WGS AF: 0.471 AC: 1639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.44
PhyloP100		-0.70

Splicing

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

Other links and lift over

dbSNP: rs6544997; hg19: chr2-47844505;