rs80358929

Positions:

• chr13-32354893-C-A
• chr13-32354893-C-G
• chr13-32354893-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):​c.7040C>A​(p.Pro2347Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,460,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11 O:1
• Conservation: PhyloP100: 1.40

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23878348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7040C>A	p.Pro2347Gln	missense_variant	14/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7040C>A	p.Pro2347Gln	missense_variant	14/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6671C>A	p.Pro2224Gln	missense_variant	14/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7040C>A		non_coding_transcript_exon_variant	13/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1460608 Hom.: 1 Cov.: 31 AF XY: 0.0000482 AC XY: 35 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Pro2347Gln variant was identified by Kote-Jarai (2011) in at least 1 of 3664 proband chromosomes from a cohort of men with prostate cancer; however, control chromosomes from healthy individuals were not evaluated in this study for comparison. The variant was also identified in the dbSNP (ID: rs80358929) “With Uncertain significance allele”, HGMD, BIC database (1X, unknown clinical significance), and the ClinVar database (submitted by BIC; submitted by Invitae with no classification provided). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Pro2347 residue is not conserved in mammals and the variant amino acid glutamine (Gln) is present in African clawed frog and fugu, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2023	Observed in an individual with breast cancer and an individual with early-onset prostate cancer, and also co-occured with a pathogenic BRCA1/2 variant in an individual with ovarian cancer (Kote-Jarai et al., 2011; Warren et al., 2011; Alsop et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7268C>A; This variant is associated with the following publications: (PMID: 22711857, 21741379, 21952622, 31131967, 31158355, 29884841, 29641532, 32377563, 31853058) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 09/08/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2023	The p.P2347Q variant (also known as c.7040C>A), located in coding exon 13 of the BRCA2 gene, results from a C to A substitution at nucleotide position 7040. The proline at codon 2347 is replaced by glutamine, an amino acid with similar properties. In one study, this alteration was identified in a man diagnosed with prostate cancer (Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4). This alteration was also observed in 1/1001 patients with non-mucinous ovarian carcinoma and classified as unclassified significance by the authors. Of note, this alteration occurred concurrently with another pathogenic BRCA1 or BRCA2 mutation in this study (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63). This alteration was identified in a patient with bilateral retinoblastoma and renal cancer who was also positive for a pathogenic mutation in the RB1 gene (Leinwand GZ et al. Urology, 2019 Sep;131:89-92). This alteration was also identified in 1/1358 unrelated, non-cancer controls in a case-control study of individuals with cutaneous melanoma and at least two independent additional primary cancers (Pritchard AL et al. PLoS ONE. 2018 Apr;13:e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2023	This missense variant replaces proline with glutamine at codon 2347 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 one individual each affected with breast, prostate and ovarian cancer (PMID: 21741379, 21952622, 22711857) and in an individual age 70 years or older without cancer in the FLOSSIES database. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 04, 2017

Variant summary: The BRCA2 c.7040C>A (p.Pro2347Gln) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 245898 control chromosomes (gnomAD). A publication, Alsop_2012 reports the variant in a patient that co-occurred with an unidentified pathogenic BRCA1/2 mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)." -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 14, 2024

This missense variant replaces proline with glutamine at codon 2347 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). A functional study has shown that this variant does not impact cell survival or drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). This variant has been reported in one individual each affected with breast, prostate and ovarian cancer (PMID: 21741379, 21952622, 22711857) and in an individual age 70 years or older without cancer in the FLOSSIES database. 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 01, 2023

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2023

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2347 of the BRCA2 protein (p.Pro2347Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer or ovarian cancer (PMID: 21952622, 22711857). ClinVar contains an entry for this variant (Variation ID: 52254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	15
DANN	Benign	0.96
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.37	N
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.20	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.24
MutPred		0.34		Gain of solvent accessibility (P = 0.0202);Gain of solvent accessibility (P = 0.0202);
MVP		0.91
MPC		0.16
ClinPred		0.81	D
GERP RS		3.0
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80358929; hg19: chr13-32929030;