2-47678251-C-A

Variant names:

• chr2-47678251-C-A
• rs17036817
• NM_001406633.1:c.2897C>A

Variant summary

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

The NM_001406633.1(MSH2):​c.2897C>A​(p.Pro966His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 456,450 control chromosomes in the GnomAD database, including 965 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P966R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (275 hom., cov: 32)
  • Exomes 𝑓: 0.041 (690 hom.)
• Consequence: MSH2 NM_001406633.1 missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.295
• Publications: 4 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 (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_001406633.1	c.2897C>A	p.Pro966His	missense_variant, splice_region_variant	Exon 18 of 19		NP_001393562.1
MSH2	NR_176241.1	n.3099C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 20 of 21
MSH2	NR_176243.1	n.2895C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5383 AN: 152030 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0510

Gnomad ASJ AF: 0.0704

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0573 AC: 7707 AN: 134504 AF XY: 0.0543

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0606

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0259

Gnomad OTH exome AF: 0.0466

GnomAD4 exome AF: 0.0409 AC: 12455 AN: 304302 Hom.: 690 Cov.: 0 AF XY: 0.0402 AC XY: 6968 AN XY: 173286

African (AFR) AF: 0.00464 AC: 40 AN: 8628

American (AMR) AF: 0.0559 AC: 1524 AN: 27272

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 660 AN: 10780

East Asian (EAS) AF: 0.314 AC: 2879 AN: 9180

South Asian (SAS) AF: 0.0321 AC: 1919 AN: 59722

European-Finnish (FIN) AF: 0.0421 AC: 538 AN: 12790

Middle Eastern (MID) AF: 0.0450 AC: 125 AN: 2780

European-Non Finnish (NFE) AF: 0.0260 AC: 4139 AN: 158922

Other (OTH) AF: 0.0443 AC: 631 AN: 14228

GnomAD4 genome AF: 0.0354 AC: 5383 AN: 152148 Hom.: 275 Cov.: 32 AF XY: 0.0381 AC XY: 2836 AN XY: 74390

African (AFR) AF: 0.00643 AC: 267 AN: 41510

American (AMR) AF: 0.0511 AC: 781 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 244 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1566 AN: 5152

South Asian (SAS) AF: 0.0423 AC: 204 AN: 4820

European-Finnish (FIN) AF: 0.0439 AC: 465 AN: 10598

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0256 AC: 1741 AN: 67998

Other (OTH) AF: 0.0463 AC: 98 AN: 2116

Alfa AF: 0.0216 Hom.: 33

Bravo AF: 0.0379

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.69
DANN	Benign	0.69
PhyloP100		0.29

Splicing

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

Other links and lift over

dbSNP: rs17036817; hg19: chr2-47905390; COSMIC: COSV107179744;