chr13-32356521-T-C

Position:

• chr13-32356521-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7529T>C​(p.Leu2510Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 7.05

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 13-32356521-T-C is Pathogenic according to our data. Variant chr13-32356521-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32356521-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7529T>C	p.Leu2510Pro	missense_variant	15/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7529T>C	p.Leu2510Pro	missense_variant	15/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7160T>C	p.Leu2387Pro	missense_variant	15/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7529T>C		non_coding_transcript_exon_variant	14/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 09, 2018	Data used in classification: The frequency of this variant is 0/138,632 individuals in gnomAD (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (25.1) (PP3-sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant has been reported in trans with another BRCA2 variant to cause Fanconi Anaemia (Hirsch et al Blood 2004; 103:2554-2559) (PM3_mod). This variant is classified on ClinVar as likely pathogenic by 2 accredited USA diagnostic laboratories (Ambry Genetics and GeneDx) (PP5_sup). Data not used in classification: There are additional reports of this variant in BIC (2), and BRCA2 LOVD (2). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2024	Variant summary: BRCA2 c.7529T>C (p.Leu2510Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251352 control chromosomes. c.7529T>C has been reported in the literature in individuals affected with Faconi Anemia/Wilms tumor/Leukemia, Breast Cancer, and HBV infection/hepatic cancer (Hirsch_2004, Lovejoy_2020, Zhao_2020). A large case-control study evaluating breast cancer genetic risk also reported this variant was enriched in the case cohorts (Dorling_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in losss of BRCA2 protein in patients cells carrying the current variant and a nonsense variant, and deleterious HDR by a gold-standard HDR assay (Hirsch_2004, Hu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 16825431, 21719596, 14670928, 35736817, 33302456, 36721989, 32957395, 33471991). ClinVar contains an entry for this variant (Variation ID: 9345). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2510 of the BRCA2 protein (p.Leu2510Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 14670928). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9345). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 21719596, 23108138, 29394989). For these reasons, this variant has been classified as Pathogenic. -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces leucine with proline at codon 2510 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 23108138, 29394989, 29884841, 33609447) and severely disrupts BRCA2 function in the rescue of viability, chromosomal aberrations and sensitivities to DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 21719596). However, a mouse model for this missense mutation and aforementioned mouse ES cell study suggest that this variant protein retains some activity and may be hypomorphic (PMID: 21719596, 35365640). This variant has been reported in one individual each affected with breast cancer (PMID: 33302456) and liver cancer (PMID: 32957395), and it has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000205). This variant also has been reported in two siblings affected with biallelic Fanconi anemia who carried a pathogenic BRCA2 truncation variant in trans (PMID: 14670928). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	Published functional studies demonstrate a damaging effect: deficient homology-directed DNA repair activity, hypersensitivity to DNA-damaging agents, deficiency in RAD51 foci formation; however reduced viability of rescued embryonic stem cells suggests this may be a hypomorphic variant (Biswas 2011, Guidugli 2018, Hart 2019, Richardson 2021); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7757T>C; This variant is associated with the following publications: (PMID: 23108138, 15645491, 22678057, 24301060, 16825431, 16115142, 25447315, 21719596, 29394989, 15689453, 32042831, 33609447, 29884841, 32957395, 12228710, 14670928) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2023	The p.L2510P pathogenic mutation (also known as c.7529T>C), located in coding exon 14 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7529. The leucine at codon 2510 is replaced by proline, an amino acid with similar properties. This alteration has been detected in two siblings with Fanconi anemia (FA) in trans with a BRCA2 pathogenic mutation (Hirsch B et al. Blood. 2004 Apr;103:2554-9; Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9). Using a mouse embryonic stem cell-based functional assay and homologous recombination-mediated DNA repair (HDR) assays, this alteration has been shown to have hypersensitivity to different DNA-damaging agents, deficiency in RAD51 foci formation and homologous recombination efficiency, increased chromosomal aberrations, and reduced binding to an essential cofactor, DSS1 (Biswas K et al. Blood. 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2023	This missense variant replaces leucine with proline at codon 2510 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in a homology-directed repair assay (PMID: 23108138, 29394989, 29884841, 33609447) and severely disrupts BRCA2 function in the rescue of viability, chromosomal aberrations and sensitivities to DNA damaging agents in Brca2-deficient mouse embryonic stem cells (PMID: 21719596). However, a mouse model for this missense mutation and aforementioned mouse ES cell study suggest that this variant protein retains some activity and may be hypomorphic (PMID: 21719596, 35365640). This variant has been reported in one individual each affected with breast cancer (PMID: 33302456) and liver cancer (PMID: 32957395), and it has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000205). This variant also has been reported in two siblings affected with biallelic Fanconi anemia who carried a pathogenic BRCA2 truncation variant in trans (PMID: 14670928). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Fanconi anemia complementation group D1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.92
MutPred		0.94		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.99
MPC		0.19
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs80358979; hg19: chr13-32930658;