NM_000059.4(BRCA2):c.3767A>C (p.His1256Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 23, 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:: RCV000561816.12

Allele description [Variation Report for NM_000059.4(BRCA2):c.3767A>C (p.His1256Pro)]

NM_000059.4(BRCA2):c.3767A>C (p.His1256Pro)

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.3767A>C (p.His1256Pro)

HGVS:

NC_000013.11:g.32338122A>C
NG_012772.3:g.27643A>C
NM_000059.4:c.3767A>CMANE SELECT
NP_000050.2:p.His1256Pro
NP_000050.3:p.His1256Pro
LRG_293t1:c.3767A>C
LRG_293:g.27643A>C
LRG_293p1:p.His1256Pro
NC_000013.10:g.32912259A>C
NM_000059.3:c.3767A>C
U43746.1:n.3995A>C

Protein change:

H1256P

Links:

dbSNP: rs80358618

NCBI 1000 Genomes Browser:

rs80358618

Molecular consequence:

NM_000059.4:c.3767A>C - 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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Homo sapiens synaptotagmin-like 5, mRNA (cDNA clone MGC:149278 IMAGE:40113205), ...
Homo sapiens synaptotagmin-like 5, mRNA (cDNA clone MGC:149278 IMAGE:40113205), complete cds
gi|124297060|gb|BC131585.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000668598	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 13, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28477318, 32885271 Citation Link,
SCV001340012	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28477318, 25741868
SCV003846856	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Dines et al. (Genet Med. 2020))	Likely benign (Mar 23, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000668598

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 13, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001340012

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 29, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003846856

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Dines et al. (Genet Med. 2020))

Likely benign
(Mar 23, 2023)

germline

curation

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

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

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

Lerner-Ellis J, Mighton C, Lazaro C, Watkins N, Di Gioacchino V, Wong A, Chang MC, Charames GS.

J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. doi: 10.1007/s00432-020-03377-6. Epub 2020 Sep 3. Erratum in: J Cancer Res Clin Oncol. 2021 Aug;147(8):2487. doi: 10.1007/s00432-020-03399-0.

PubMed [citation]

PMID:: 32885271

Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.

Gabaldó Barrios X, Sarabia Meseguer MD, Marín Vera M, Sánchez Bermúdez AI, Macías Cerrolaza JA, Sánchez Henarejos P, Zafra Poves M, García Hernández MR, Cuevas Tortosa E, Aliaga Baño Á, Castillo Guardiola V, Martínez Hernández P, Tovar Zapata I, Martínez Barba E, Ayala de la Peña F, Alonso Romero JL, Noguera Velasco JA, Ruiz Espejo F.

Fam Cancer. 2017 Oct;16(4):477-489. doi: 10.1007/s10689-017-9985-x.

PubMed [citation]

PMID:: 28477318

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000668598.5

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

Description

The p.H1256P variant (also known as c.3767A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3767. The histidine at codon 1256 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of Spanish hereditary breast and ovarian cancer families (Gabaldó Barrios X et al. Fam Cancer, 2017 10;16:477-489). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 147, 871–879). This amino acid position is poorly conserved in available vertebrate species. 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, SCV001340012.3

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

Description

This missense variant replaces histidine with proline at codon 1256 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 1 individual affected with breast and/or ovarian cancer (PMID: 28477318). This variant has not been identified 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 University of Washington Department of Laboratory Medicine, University of Washington, SCV003846856.1

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

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

#	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: Sep 29, 2024

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