NM_000059.4(BRCA2):c.241T>A (p.Phe81Ile) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jun 8, 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:: RCV000031366.9

Allele description [Variation Report for NM_000059.4(BRCA2):c.241T>A (p.Phe81Ile)]

NM_000059.4(BRCA2):c.241T>A (p.Phe81Ile)

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.241T>A (p.Phe81Ile)

Other names:

p.F81I:TTC>ATC

HGVS:

NC_000013.11:g.32319250T>A
NG_012772.3:g.8771T>A
NG_017006.2:g.1114A>T
NM_000059.4:c.241T>AMANE SELECT
NP_000050.2:p.Phe81Ile
NP_000050.3:p.Phe81Ile
LRG_293t1:c.241T>A
LRG_293:g.8771T>A
LRG_293p1:p.Phe81Ile
NC_000013.10:g.32893387T>A
NM_000059.3:c.241T>A
U43746.1:n.469T>A

Nucleotide change:

469T>A

Protein change:

F81I

Links:

dbSNP: rs80358507

NCBI 1000 Genomes Browser:

rs80358507

Molecular consequence:

NM_000059.4:c.241T>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

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Profile neighbors for GEO Profiles (Select 111594283) (172)
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High grade prostate cancer
High grade prostate cancer
Accession: GDS5072

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053971	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Benign (Jun 4, 2010)	germline	clinical testing
SCV000146428	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Uncertain significance (Feb 20, 2004)	germline	clinical testing
SCV000784869	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jan 18, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21952622, 25348012 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV002758576	Human Genetics Bochum, Ruhr University Bochum	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004846751	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21952622, 33471991, 35979650, 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	1	not provided	not provided	1	not provided	clinical testing
Western European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations.

Martelotto LG, Ng CK, De Filippo MR, Zhang Y, Piscuoglio S, Lim RS, Shen R, Norton L, Reis-Filho JS, Weigelt B.

Genome Biol. 2014 Oct 28;15(10):484. doi: 10.1186/s13059-014-0484-1.

PubMed [citation]

PMID:: 25348012
PMCID:: PMC4232638

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.

Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N, Guy M, Edwards S, O'Brien L, Sawyer E, Hall A, Wilkinson R, Dadaev T, Goh C, Easton D; UKGPCS Collaborators., Goldgar D, Eeles R.

Br J Cancer. 2011 Oct 11;105(8):1230-4. doi: 10.1038/bjc.2011.383. Epub 2011 Sep 27.

PubMed [citation]

PMID:: 21952622
PMCID:: PMC3208504

See all PubMed Citations (5)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000053971.3

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000146428.1

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

From Counsyl, SCV000784869.2

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

#	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 Human Genetics Bochum, Ruhr University Bochum, SCV002758576.1

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

Description

ACMG criteria used to clasify this variant: PM2, 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		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004846751.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces phenylalanine with isoleucine at codon 81 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). In a functional study, this variant showed 72% homology-directed repair capacity of wild-type BRCA2 (PMID: 35979650). This variant has been detected in a breast cancer case-control meta-analysis in 6/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001289) and also in an individual affected with prostate cancer (PMID: 21952622). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database and in 6/251364 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: Oct 20, 2024

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