NM_000059.4(BRCA2):c.3893T>C (p.Ile1298Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 8, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000566464.7

Allele description [Variation Report for NM_000059.4(BRCA2):c.3893T>C (p.Ile1298Thr)]

NM_000059.4(BRCA2):c.3893T>C (p.Ile1298Thr)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.3893T>C (p.Ile1298Thr)

HGVS:

NC_000013.11:g.32338248T>C
NG_012772.3:g.27769T>C
NM_000059.4:c.3893T>CMANE SELECT
NP_000050.2:p.Ile1298Thr
NP_000050.3:p.Ile1298Thr
LRG_293t1:c.3893T>C
LRG_293:g.27769T>C
LRG_293p1:p.Ile1298Thr
NC_000013.10:g.32912385T>C
NM_000059.3:c.3893T>C
U43746.1:n.4121T>C

Protein change:

I1298T

Links:

dbSNP: rs80358633

NCBI 1000 Genomes Browser:

rs80358633

Molecular consequence:

NM_000059.4:c.3893T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000666137	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12491499, 16234499, 33471991 Citation Link,
SCV003848508	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Dines et al. (Genet Med. 2020))	Likely benign (Mar 23, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000666137

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 8, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV003848508

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Dines et al. (Genet Med. 2020))

Likely benign
(Mar 23, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers.

Adem C, Reynolds C, Soderberg CL, Slezak JM, McDonnell SK, Sebo TJ, Schaid DJ, Myers JL, Sellers TA, Hartmann LC, Jenkins RB.

Cancer. 2003 Jan 1;97(1):1-11.

PubMed [citation]

PMID:: 12491499

Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry.

Nanda R, Schumm LP, Cummings S, Fackenthal JD, Sveen L, Ademuyiwa F, Cobleigh M, Esserman L, Lindor NM, Neuhausen SL, Olopade OI.

JAMA. 2005 Oct 19;294(15):1925-33.

PubMed [citation]

PMID:: 16234499

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000666137.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.I1298T variant (also known as c.3893T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3893. The isoleucine at codon 1298 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in familial breast cancer cohorts (Adem C et al. Cancer, 2003 Jan;97:1-11; Nanda R et al. JAMA, 2005 Oct;294:1925-33). In one study, this variant was reported in 2/60,466 breast cancer cases as well as in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003848508.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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