NM_000059.4:c.7958T>C

Variant names:

• chr13-32362675-T-C
• rs80359022
• NM_000059.4:c.7958T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7958T>C​(p.Leu2653Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L2653L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 7.93

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 Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 13-32362675-T-C is Pathogenic according to our data. Variant chr13-32362675-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32362675-T-C is described in Lovd as [Pathogenic]. Variant chr13-32362675-T-C is described in Lovd as [Likely_pathogenic]. Variant chr13-32362675-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7958T>C	p.Leu2653Pro	missense_variant	Exon 17 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7958T>C	p.Leu2653Pro	missense_variant	Exon 17 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7589T>C	p.Leu2530Pro	missense_variant	Exon 17 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*16T>C		non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*16T>C		3_prime_UTR_variant	Exon 16 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 28, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.7958T>C (p.Leu2653Pro) results in a non-conservative amino acid change located in the helical domain (IPR015252) of 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 251260 control chromosomes (gnomAD). c.7958T>C has been reported in the literature in multiple individuals affected with breast and ovarian cancers, including those with a personal and/or family history of these cancers (e.g. Carney_2010, Bernards_2016, Lang_2017, Carter_2018, Rebbeck_2018). These data indicate that the variant is likely associated with disease. Multiple functional studies report experimental evidence evaluating an impact on protein function and show a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Biswas_2012, Guidugli_2012, Ikegami_2020). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=5) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2653 of the BRCA2 protein (p.Leu2653Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22678057, 29061967). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52447). Invitae Evidence Modeling incorporating data from in vitro 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: 22678057). For these reasons, this variant has been classified as Pathogenic. -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu2653Pro variant in BRCA2 has been reported in at least 3 individuals with breast cancer (Easton 2007, BIC database) and was absent from large population studies, but has been reported in Clinvar (Variation ID: 52447). In vitro assays provide some evidence that this variant impacts protein function (Biswas 2012, Guidugli 2014, Bernards 2016, Guidugli 2018, Mesman 2018); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting. -

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Feb 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history consistent with pathogenic variants in this gene, and is shown to segregate with disease in multiple families (Carney 2010, Biswas 2012, Bernards 2016); Published functional studies demonstrate a damaging effect: defective homology-directed DNA repair activity, sensitivity to DNA-damaging agents, and inability to rescue lethality in BRCA2-deficient mouse embryonic stem cells (Biswas 2012, Guidugli 2013, Mesman 2018, Hart 2019, Ikegami 2020, Richardson 2021); Multifactorial studies based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants predict this variant to be deleterious (Lindor 2012); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); Also known as 8186T>C; This variant is associated with the following publications: (PMID: 17924331, 11698567, 21218378, 24333842, 29394989, 19043619, 23108138, 22678057, 24323938, 18451181, 26718727, 25447315, 27067391, 28339459, 29988080, 32444794, 29884841, 33964450, 30702160, 31825140, 32719484, 29446198, 33609447, 30696104, 21990134, 12228710) -

Jan 03, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported in individuals and families with breast and/or ovarian cancer in the published literature (PMID: 26718727 (2016), 22678057 (2012)). Multifactorial analyses strongly support pathogenicity of this variant (PMID: 23108138 (2013), 21990134 (2012), 19043619 (2008), 17924331 (2007). Assessment of experimental evidence suggest the variant is detrimental to BRCA2 protein function (PMID: 29394989 (2018), 23108138 (2013), 22678057 (2012), 18451181 (2008)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L2653P variant (also known as c.7958T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7958. The leucine at codon 2653 is replaced by proline, an amino acid with similar properties. This alteration has been detected in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Bernards SS et al. Gynecol. Oncol. 2016 Feb;140:221-5; Flaum N et al. Genet Med, 2022 Dec;24:2578-2586). The p.L2653P variant is located in the DNA binding domain of BRCA2 and has been shown in multiple studies to significantly decrease DNA damage repair activity (Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Biswas K et al. Hum. Mol. Genet. 2012 Sep;21:3993-4006; 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; Mesman RLS et al. Genet. Med., 2019 02;21:293-302; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). 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 variant is likely to be pathogenic. -

Apr 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 2653 in the DNA binding domain 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 shown that this variant results in the loss of homology-directed DNA repair activity of the BRCA2 protein (PMID: 18451181, 22678057, 23108138, 24323938, 29394989, 33609447). This variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 24333842, 26718727, 29371908; Color internal data). 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 Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Aug 28, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Jan 01, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 08-12-2020 by Lab or GTR ID 506138. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.90
MutPred		0.85		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.99
MPC		0.19
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.90

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: rs80359022; hg19: chr13-32936812;