NM_000059.4(BRCA2):c.241T>A (p.Phe81Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 27, 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:: RCV000217504.13

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]

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
SCV000272958	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jan 7, 2019)	germline	clinical testing	Citation Link,
SCV000683483	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21952622, 33471991, 35979650, 25741868
SCV002535500	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jan 4, 2022)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 33471991, 21952622, 31464824 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272958

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jan 7, 2019)

germline

clinical testing

Citation Link,

SCV000683483

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 27, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002535500

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jan 4, 2022)

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

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.

Thomassen M, Mesman RLS, Hansen TVO, Menendez M, Rossing M, Esteban-Sánchez A, Tudini E, Törngren T, Parsons MT, Pedersen IS, Teo SH, Kruse TA, Møller P, Borg Å, Jensen UB, Christensen LL, Singer CF, Muhr D, Santamarina M, Brandao R, Andresen BS, Feng BJ, et al.

Hum Mutat. 2022 Dec;43(12):1921-1944. doi: 10.1002/humu.24449. Epub 2022 Oct 23.

PubMed [citation]

PMID:: 35979650
PMCID:: PMC10946542

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000272958.5

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000683483.5

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

From Sema4, Sema4, SCV002535500.1

#	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: Oct 20, 2024

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