chr2-47403280-C-T

Variant names:

• chr2-47403280-C-T
• rs757892928
• NM_000251.3:c.89C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001406654.1(MSH2):​c.-252C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,447,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MSH2 NM_001406654.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 7.26
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• BP6: Variant 2-47403280-C-T is Benign according to our data. Variant chr2-47403280-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185140.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406654.1. 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.89C>T	p.Pro30Leu	missense	Exon 1 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406654.1		c.-252C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001393583.1
	MSH2	NM_001406656.1		c.-907C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001393585.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 1 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.89C>T	p.Pro30Leu	missense	Exon 1 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.89C>T	p.Pro30Leu	missense	Exon 1 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000455 AC: 1 AN: 219710 AF XY: 0.00000835

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1447798 Hom.: 0 Cov.: 31 AF XY: 0.00000974 AC XY: 7 AN XY: 719044

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

American (AMR) AF: 0.00 AC: 0 AN: 41898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.00 AC: 0 AN: 83718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1107240

Other (OTH) AF: 0.0000167 AC: 1 AN: 59862

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Lynch syndrome 1 (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.77
Sift	Benign	0.59	T
Sift4G	Benign	0.45	T
Polyphen		0.76	P
Vest4		0.70
MutPred		0.65		Loss of disorder (P = 0.042)
MVP		0.91
MPC		0.0092
ClinPred		0.97	D
GERP RS		5.7
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.46
gMVP		0.59
Mutation Taster		=37/63	disease causing

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: rs757892928; hg19: chr2-47630419;