rs10183143

Variant names:

• chr2-47466898-T-C
• rs10183143
• NM_000251.3:c.1661+90T>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.1661+90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,402,120 control chromosomes in the GnomAD database, including 1,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.031 (102 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1222 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 1.67
• Publications: 10 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), Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 2-47466898-T-C is Benign according to our data. Variant chr2-47466898-T-C is described in ClinVar as Benign. ClinVar VariationId is 90723.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1661+90T>C		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1661+90T>C		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1661+90T>C		intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1661+90T>C		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1661+90T>C		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1712+90T>C		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4751 AN: 152236 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0459

Gnomad OTH AF: 0.0449

GnomAD4 exome AF: 0.0394 AC: 49184 AN: 1249766 Hom.: 1222 AF XY: 0.0392 AC XY: 24761 AN XY: 631820

African (AFR) AF: 0.00731 AC: 206 AN: 28164

American (AMR) AF: 0.0328 AC: 1411 AN: 43038

Ashkenazi Jewish (ASJ) AF: 0.0847 AC: 2073 AN: 24472

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38186

South Asian (SAS) AF: 0.0108 AC: 863 AN: 79574

European-Finnish (FIN) AF: 0.0129 AC: 677 AN: 52602

Middle Eastern (MID) AF: 0.0634 AC: 239 AN: 3768

European-Non Finnish (NFE) AF: 0.0447 AC: 41424 AN: 927004

Other (OTH) AF: 0.0432 AC: 2286 AN: 52958

GnomAD4 genome AF: 0.0312 AC: 4747 AN: 152354 Hom.: 102 Cov.: 33 AF XY: 0.0293 AC XY: 2180 AN XY: 74508

African (AFR) AF: 0.00851 AC: 354 AN: 41580

American (AMR) AF: 0.0429 AC: 657 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4828

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0458 AC: 3118 AN: 68038

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0403 Hom.: 113

Bravo AF: 0.0343

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lynch syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.67
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs10183143; hg19: chr2-47694037;