NM_000059.4(BRCA2):c.9925G>A (p.Glu3309Lys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jul 1, 2024
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:: RCV000195387.26

Allele description [Variation Report for NM_000059.4(BRCA2):c.9925G>A (p.Glu3309Lys)]

NM_000059.4(BRCA2):c.9925G>A (p.Glu3309Lys)

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.9925G>A (p.Glu3309Lys)

Other names:

p.E3309K:GAA>AAA

HGVS:

NC_000013.11:g.32398438G>A
NG_012772.3:g.87959G>A
NM_000059.4:c.9925G>AMANE SELECT
NP_000050.2:p.Glu3309Lys
NP_000050.3:p.Glu3309Lys
LRG_293t1:c.9925G>A
LRG_293:g.87959G>A
LRG_293p1:p.Glu3309Lys
NC_000013.10:g.32972575G>A
NM_000059.3:c.9925G>A
U43746.1:n.10153G>A
p.E3309K

Nucleotide change:

10153G>A

Protein change:

E3309K

Links:

dbSNP: rs80359251

NCBI 1000 Genomes Browser:

rs80359251

Molecular consequence:

NM_000059.4:c.9925G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000210521	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Nov 27, 2020)	germline	clinical testing	Citation Link,
SCV000296744	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely benign (Nov 23, 2022)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 28873162, 34196900, 32467295, 31131967, 28843361, 26689913, 24728327, 26467025, 26295337
SCV004847666	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 10, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26287763, 25741868
SCV005092803	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Jul 1, 2024)	germline	clinical testing	Citation Link

Help

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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, Pradhan N, Arnold A, Walsh MF, Li Y, Balakrishnan AR, Syed A, Prasad M, Nafa K, Carlo MI, Cadoo KA, Sheehan M, Fleischut MH, Salo-Mullen E, Trottier M, Lipkin SM, Lincoln A, et al.

JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137. Erratum in: JAMA. 2018 Dec 11;320(22):2381. doi: 10.1001/jama.2018.17511.

PubMed [citation]

PMID:: 28873162
PMCID:: PMC5611881

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer.

Ren M, Orozco A, Shao K, Albanez A, Ortiz J, Cao B, Wang L, Barreda L, Alvarez CS, Garland L, Wu D, Chung CC, Wang J, Frone M, Ralon S, Argueta V, Orozco R, Gharzouzi E, Dean M.

Breast Cancer Res Treat. 2021 Sep;189(2):533-539. doi: 10.1007/s10549-021-06305-5. Epub 2021 Jul 1. Erratum in: Breast Cancer Res Treat. 2022 Jan;191(1):227. doi: 10.1007/s10549-021-06373-7.

PubMed [citation]

PMID:: 34196900
PMCID:: PMC8357728

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000210521.13

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

Description

This variant is associated with the following publications: (PMID: 25451944, 24728327, 26689913, 28873162, 26295337, 26287763)

#	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		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296744.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847666.1

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

Description

The p.Glu3309Lys variant in BRCA2 has been reported in one individual with breast cancer and 2 individuals with other cancers (Pal 2015 PMID: 26287763, Parry 2017 PMID: 28843361, Mandelker 2017 PMID: 28873162). It has also been identified in 0.08% (20/24958) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV005092803.3

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

Description

BRCA2: BP4

#	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

Last Updated: Nov 3, 2024

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