2-47439699-T-C

Variant names:

• chr2-47439699-T-C
• rs17036577
• NM_000251.3:c.1277-5849T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.1277-5849T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0879 in 152,068 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.088 (627 hom., cov: 31)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.582
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-47439699-T-C is Benign according to our data. Variant chr2-47439699-T-C is described in ClinVar as Benign. ClinVar VariationId is 90607.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1277-5849T>C		intron_variant	Intron 7 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1277-5849T>C		intron_variant	Intron 7 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0877 AC: 13328 AN: 151948 Hom.: 622 Cov.: 31

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0816

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0863

Gnomad OTH AF: 0.0951

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

GnomAD4 genome AF: 0.0879 AC: 13360 AN: 152068 Hom.: 627 Cov.: 31 AF XY: 0.0874 AC XY: 6500 AN XY: 74350

African (AFR) AF: 0.100 AC: 4162 AN: 41468

American (AMR) AF: 0.0560 AC: 855 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 432 AN: 3464

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5174

South Asian (SAS) AF: 0.124 AC: 599 AN: 4822

European-Finnish (FIN) AF: 0.0816 AC: 864 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0863 AC: 5867 AN: 67970

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.0441 Hom.: 34

Bravo AF: 0.0859

Asia WGS AF: 0.0760 AC: 265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.93
DANN	Benign	0.72
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17036577; hg19: chr2-47666838;