NM_000059.4(BRCA2):c.9839C>A (p.Pro3280His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 1, 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:: RCV000130774.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.9839C>A (p.Pro3280His)]

NM_000059.4(BRCA2):c.9839C>A (p.Pro3280His)

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.9839C>A (p.Pro3280His)

HGVS:

NC_000013.11:g.32398352C>A
NG_012772.3:g.87873C>A
NM_000059.4:c.9839C>AMANE SELECT
NP_000050.2:p.Pro3280His
NP_000050.3:p.Pro3280His
LRG_293t1:c.9839C>A
LRG_293:g.87873C>A
LRG_293p1:p.Pro3280His
NC_000013.10:g.32972489C>A
NM_000059.3:c.9839C>A
U43746.1:n.10067C>A
p.P3280H

Nucleotide change:

10067C>A

Protein change:

P3280H

Links:

dbSNP: rs80359246

NCBI 1000 Genomes Browser:

rs80359246

Molecular consequence:

NM_000059.4:c.9839C>A - 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
SCV000185667	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 1, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18593900, 27062684, 29684080, 31228304, 35402282 Citation Link,
SCV000911112	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 11, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002532064	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Apr 4, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 27062684, 31228304, 18593900 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185667

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 1, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000911112

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Sep 11, 2017)

germline

clinical testing

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

SCV002532064

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Apr 4, 2021)

germline

curation

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

Citation Link

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

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations.

Yehia L, Ni Y, Sesock K, Niazi F, Fletcher B, Chen HJL, LaFramboise T, Eng C.

PLoS Genet. 2018 Apr;14(4):e1007352. doi: 10.1371/journal.pgen.1007352.

PubMed [citation]

PMID:: 29684080
PMCID:: PMC5933810

Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives.

Abdel-Razeq H, Tamimi F, Abujamous L, Abdel-Razeq R, Abunasser M, Edaily S, Abdulelah H, Khashabeh RA, Bater R.

Front Oncol. 2022;12:673094. doi: 10.3389/fonc.2022.673094.

PubMed [citation]

PMID:: 35402282
PMCID:: PMC8989924

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000185667.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.P3280H variant (also known as c.9839C>A), located in coding exon 26 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9839. The proline at codon 3280 is replaced by histidine, an amino acid with similar properties. In a study of 1854 high-risk BR/OV cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71). Additionally, this alteration was identified in a cohort of unselected individuals pursuing BRCA1/2 testing in Turkey (Bisgin A et al. Breast J, 2019 09;25:1029-1033). This alteration was also detected in 1/1197 individuals diagnosed with breast cancer (Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This amino acid position is highly conserved on sequence alignment. 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 Color Diagnostics, LLC DBA Color Health, SCV000911112.1

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

#	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 Sema4, Sema4, SCV002532064.1

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

#	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: Jul 15, 2024

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