2-47414387-T-C

Variant names:

• chr2-47414387-T-C
• rs1021303606
• NM_000251.3:c.911T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001406659.1(MSH2):​c.-558T>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,458,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_001406659.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 5.53
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41622716).
• BP6: Variant 2-47414387-T-C is Benign according to our data. Variant chr2-47414387-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455623.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406659.1. 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.911T>C	p.Ile304Thr	missense	Exon 5 of 16	NP_000242.1
	MSH2	NM_001406659.1		c.-558T>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 17	NP_001393588.1
	MSH2	NM_001406660.1		c.-755T>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 19	NP_001393589.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.911T>C	p.Ile304Thr	missense	Exon 5 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.911T>C	p.Ile304Thr	missense	Exon 5 of 16	ENSP00000384199.1
	MSH2	ENST00000918107.1		c.962T>C	p.Ile321Thr	missense	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458994 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 725786

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110532

Other (OTH) AF: 0.0000166 AC: 1 AN: 60178

GnomAD4 genome Cov.: 28

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	1	-	MSH2-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.20	N
PhyloP100		5.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.46	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.59
MutPred		0.47		Gain of phosphorylation at I304 (P = 0.0716)
MVP		0.93
MPC		0.0060
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.16
Mutation Taster		=63/37	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: rs1021303606; hg19: chr2-47641526;