chr2-47408384-C-CT

Variant names:

• chr2-47408384-C-CT
• rs746333570
• NM_000251.3:c.212-4dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000251.3(MSH2):​c.212-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 143,858 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.21 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.95
• Publications: 1 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: 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 -8 ACMG points.

• BP6: Variant 2-47408384-C-CT is Benign according to our data. Variant chr2-47408384-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 491795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.212-4dupT		splice_region intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.212-4dupT		splice_region intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.212-4dupT		splice_region 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.212-17_212-16insT		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.212-17_212-16insT		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.212-17_212-16insT		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 270 AN: 143802 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000534

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00140

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000401

Gnomad SAS AF: 0.0115

Gnomad FIN AF: 0.00910

Gnomad MID AF: 0.00331

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00307

GnomAD2 exomes AF: 0.204 AC: 21878 AN: 107442 AF XY: 0.208

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.234

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.208 AC: 194346 AN: 932154 Hom.: 0 Cov.: 0 AF XY: 0.207 AC XY: 95722 AN XY: 462300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.209 AC: 4589 AN: 21966

American (AMR) AF: 0.188 AC: 5649 AN: 30112

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 3667 AN: 17280

East Asian (EAS) AF: 0.206 AC: 5342 AN: 25934

South Asian (SAS) AF: 0.202 AC: 11221 AN: 55436

European-Finnish (FIN) AF: 0.172 AC: 6117 AN: 35532

Middle Eastern (MID) AF: 0.139 AC: 582 AN: 4180

European-Non Finnish (NFE) AF: 0.212 AC: 148903 AN: 702470

Other (OTH) AF: 0.211 AC: 8276 AN: 39244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00190 AC: 273 AN: 143858 Hom.: 1 Cov.: 31 AF XY: 0.00202 AC XY: 141 AN XY: 69822

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000558 AC: 22 AN: 39438

American (AMR) AF: 0.00147 AC: 21 AN: 14266

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3354

East Asian (EAS) AF: 0.000402 AC: 2 AN: 4972

South Asian (SAS) AF: 0.0117 AC: 53 AN: 4518

European-Finnish (FIN) AF: 0.00910 AC: 81 AN: 8900

Middle Eastern (MID) AF: 0.00362 AC: 1 AN: 276

European-Non Finnish (NFE) AF: 0.00132 AC: 86 AN: 65280

Other (OTH) AF: 0.00305 AC: 6 AN: 1966

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0849 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
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: rs746333570; hg19: chr2-47635523; COSMIC: COSV51878521;