rs80359052

chr13-32363294-G-Achr13-32363294-G-Cchr13-32363294-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):c.8092G>A(p.Ala2698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2698G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:9
• Conservation: PhyloP100: 0.00700

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03287059).
• BP6: Variant 13-32363294-G-A is Benign according to our data. Variant chr13-32363294-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38138.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=8}. Variant chr13-32363294-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8092G>A	p.Ala2698Thr	missense_variant	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8092G>A	p.Ala2698Thr	missense_variant	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251318 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135822

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727216

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74424

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2023	In the published literature, the variant has been reported in individuals affected with or considered to be high risk for breast and/or ovarian cancer (PMIDs: 21156238 (2010), 26287763 (2015), 29854292 (2018), 30982232 (2019), 32658311 (2021), 32885271 (2021), 33875706 (2021), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)), as well as in healthy individuals (PMIDs: 9971877 (1999), 32658311 (2021), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.0002 (4/19946 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Dec 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 19, 2017	The BRCA2 c.8092G>A;p.Ala2698Thr variant has been described in the medical literature in an individual with breast cancer and a family history of cancer (Manguoglu 2010). The variant is listed in the ClinVar database (Variation ID: 38138), the dbSNP variant database (rs80359052), and the Genome Aggregation Database with an allele frequency of 0.004331 percent (12/277058 alleles). The amino acid at this position is weakly conserved across species, with several mammalian species with threonine at this position, and computational algorithms (AlignGVGD, SIFT, MutationTaster) predict this variant is tolerated. Considering available information, the clinical significance cannot be determined with certainty. References: Manguoglu E et al. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients. Cancer Genet Cytogenet. 2010 Dec;203(2):230-7. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 13, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 23, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Nov 30, 1998	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS1(Strong)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2021	Variant summary: BRCA2 c.8092G>A (p.Ala2698Thr) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251318 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8092G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as other cancer types without evidence for causality (example, Dorling_2021, Kim_2021, Akcay_2020, Encinas_2018, Wang_2018, Dong_2018, Lu_2015, Pal_2015, Kandoth_2013, Manguoglu_2010, Manguoglu_2010, Wagner_1999). At-least one of these publications reported re-classification of this variant from a VUS to likely benign supported by ACMG guidelines and a validated multifactorial probability model (Lee_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.1321_1324delACTT, p.Thr441GlnfsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments (VUS=5, Likely Benign=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ala2698Thr variant was identified in in 4 of 5634 proband chromosomes (frequency: 0.0007) from individuals or families with breast or ovarian cancer and was present in 1 of 290 control chromosomes (frequency: 0.003) from healthy individuals (Lee 2018, Manguoğlu 2010, Pal 2015, Wagner 1999, Encinas 2018). The variant was also identified in dbSNP (ID: rs80359052) as "with Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Sharing Clinical Reports Project (SCRP) and six other submitters; and as likely benign by Ambry Genetics, GeneDx and one other submitter), and the LOVD 3.0 database. The variant was not identified in the UMD-LSDB database. It was identified in control databases in 12 of 277058 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 24034 chromosomes (freq: 0.0003), Other in 1 of 6460 chromosomes (freq: 0.0002), and East Asian in 5 of 18860 chromosomes (freq: 0.0003), while the variant was not observed in the Latino, European, Ashkenazi Jewish, Finnish or South Asian populations. The p.Ala2698 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 uncertain significance. -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2024

ACMG codes applied following ENIGMA VCEP rules: BS1_SUP, BS2_SUP, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	4.5
Dann	Benign	0.13
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0044	N
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.57	N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.13
MVP		0.75
MPC		0.020
ClinPred		0.0059	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.20

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: rs80359052; hg19: chr13-32937431; COSMIC: COSV66455423; COSMIC: COSV66455423;