13-32363216-A-G

Position:

• chr13-32363216-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_000059.4(BRCA2):​c.8014A>G​(p.Ile2672Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 0.876

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36564702).
• BP6: Variant 13-32363216-A-G is Benign according to our data. Variant chr13-32363216-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 38135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32363216-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8014A>G	p.Ile2672Val	missense_variant	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8014A>G	p.Ile2672Val	missense_variant	18/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7645A>G	p.Ile2549Val	missense_variant	18/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*72A>G		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*72A>G		3_prime_UTR_variant	17/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000120 AC: 3 AN: 250930 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135624

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000597

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

Gnomad4 AFR AF: 0.0000241

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: 0.0000277 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Jan 17, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ile2672Val variant was identified in 1 of 878 proband chromosomes (frequency: 0.001) from individuals or families with triple-negative breast cancer (Wong-Brown 2015). The variant was also identified in dbSNP (ID: rs80359037) as "With other allele ", ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Color Genomics, SCRP and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by Invitae and BIC), Clinvitae, MutDB, LOVD 3.0 (3x ), and in BIC (3x unknown clinical importance) databases. The variant was not identified in GeneInsight-COGR, Cosmic, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 4 of 276724 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 24034 chromosomes (freq: 0.0001), European in 1 of 126390 chromosomes (freq: 0.00001), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ile2672 residue is not conserved in mammals and 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In a functional study a homology-directed DNA repair assay found the variant to act similar to a neutral variant or wild-type protein with a 99% probability of neutrality (Guidugli 2018). In addition, protein likelihood ratio in favor of protein loss of function of the variant is 0.246, and predicted to be neutral (Karchin 2008). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 17, 2011	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2017	Variant summary: The BRCA2 8014A>G (p.Ile2672Val) variant, alternatively also known as 8242A>G, involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 2/3 in silico tools (SNPs&GO not captured due to low reliability index). Based on the protein likelihood ratio calculation this variant was predicted to be neutral (Karching et al., 2008). This variant was found in 1/120556 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in several HBOC patients/families in literature and clinical databases. This variant was found not to cosegregate with disease amongst nine unrelated families (Miller-Samuel et al, 2011). Although details of genotypic and phenotypic information is not provided for family members, this study strongly supports for the benign outcome. In addition, the variant's co-occurrence with another BRCA1/2 pathogenic variant has also been reported (Azzollini_2016), further supporting the benign outcome. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance (3) as well as likely benign (3). Taken together, this variant is currently classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28873162, 19043619, 25682074, 28525389, 27062684, 29394989, 21810505, 31131967, 29884841) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2017	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, no assertion criteria provided	clinical testing	True Health Diagnostics	May 03, 2018	- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.051	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.30	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.025	D;D
Vest4		0.40
MutPred		0.66		Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);
MVP		0.85
MPC		0.080
ClinPred		0.42	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.28

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: rs80359037; hg19: chr13-32937353;