NM_000059.4(BRCA2):c.9905G>A (p.Arg3302Lys) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Feb 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000083164.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.9905G>A (p.Arg3302Lys)]

NM_000059.4(BRCA2):c.9905G>A (p.Arg3302Lys)

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.9905G>A (p.Arg3302Lys)

HGVS:

NC_000013.11:g.32398418G>A
NG_012772.3:g.87939G>A
NM_000059.4:c.9905G>AMANE SELECT
NP_000050.2:p.Arg3302Lys
NP_000050.3:p.Arg3302Lys
LRG_293t1:c.9905G>A
LRG_293:g.87939G>A
LRG_293p1:p.Arg3302Lys
NC_000013.10:g.32972555G>A
NM_000059.3:c.9905G>A
U43746.1:n.10133G>A

Nucleotide change:

10133G>A

Protein change:

R3302K

Links:

dbSNP: rs80359249

NCBI 1000 Genomes Browser:

rs80359249

Molecular consequence:

NM_000059.4:c.9905G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

Recent activity

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EC1CBA001ZA04.b1 Xenopus tropicalis xtbs plasmid library Xenopus tropicalis cDNA...
EC1CBA001ZA04.b1 Xenopus tropicalis xtbs plasmid library Xenopus tropicalis cDNA clone xtbs01P24 3', mRNA sequence
gi|45851041|gnl|dbEST|22183221|gb|C 84.1|

Nucleotide
Rattus norvegicus DNA for nucleoside diphosphate kinase alpha isoform, partial c...
Rattus norvegicus DNA for nucleoside diphosphate kinase alpha isoform, partial cds
gi|1729426|dbj|D89068.1|

Nucleotide
Atxn7l1os1 ataxin 7-like 1, opposite strand 1 [Mus musculus]
Atxn7l1os1 ataxin 7-like 1, opposite strand 1 [Mus musculus]
Gene ID:100504517

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000115238	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Likely benign (Jun 14, 2012)	germline	clinical testing
SCV000145727	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Uncertain significance (May 29, 2002)	germline	clinical testing
SCV000785011	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Mar 15, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004846244	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12491499, 28843361, 31131967, 33471991, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	3	not provided	not provided	3	not provided	clinical testing
Central/Eastern European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Western European	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

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

Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma.

Parry EM, Gable DL, Stanley SE, Khalil SE, Antonescu V, Florea L, Armanios M.

J Thorac Oncol. 2017 Nov;12(11):1673-1678. doi: 10.1016/j.jtho.2017.08.011. Epub 2017 Aug 24.

PubMed [citation]

PMID:: 28843361
PMCID:: PMC5659909

See all PubMed Citations (5)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000115238.4

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	3	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000145727.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	Central/Eastern European	1	not provided	not provided	clinical testing	not provided
3	Western European	1	not provided	not provided	clinical testing	not provided

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

From Counsyl, SCV000785011.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004846244.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces arginine with lysine at codon 3302 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast cancer and one unaffected individual (PMID: 12491499, 33471991; Leiden Open Variation Database DB-ID BRCA2_002114) and in an individual affected with adenocarcinoma (PMID: 28843361). A multifactorial analysis has reported tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.77, 1.1022 and 0.1339, respectively (PMID: 31131967). This variant has been identified in 2/251204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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