NM_000059.4:c.3310A>C

Variant names:

• chr13-32337665-A-C
• rs80358577
• NM_000059.4:c.3310A>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.3310A>C​(p.Thr1104Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000762 in 1,442,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 6.88

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 -1 ACMG points.

• BP6: Variant 13-32337665-A-C is Benign according to our data. Variant chr13-32337665-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51448.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3310A>C	p.Thr1104Pro	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3310A>C	p.Thr1104Pro	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2941A>C	p.Thr981Pro	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3310A>C		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000170 AC: 4 AN: 235948 Hom.: 0 AF XY: 0.0000235 AC XY: 3 AN XY: 127636

Gnomad AFR exome AF: 0.00

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: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1442990 Hom.: 0 Cov.: 33 AF XY: 0.00000978 AC XY: 7 AN XY: 715960

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: 0.00000906

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Sep 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with proline at codon 1104 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 at least two individuals affected with breast or ovarian cancer and in two unaffected individuals (DOI: 10.5603/OCP.2020.0026, 10.1515/tjb-2019-0424, PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008063, 36605468). This variant has been identified in 4/235948 chromosomes 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. -

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1104P variant (also known as c.3310A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3310. The threonine at codon 1104 is replaced by proline, an amino acid with highly similar properties. This variant has been reported in individuals with breast cancer (Akcay IM et al. Int J Cancer. 2021 Jan;148(2):285-295; Peker Ey&uuml;bolu et al. OMICS. 2020 Jan;24(1):5-15; Subaolu A et al. Eur J Breast Health. 2023 Jan;19(1):55-69; Corso G et al. JAMA Netw Open. 2024 Apr;7(4):e247862), and also in healthy control subjects (Akcay IM et al. Int J Cancer. 2021 Jan;148(2):285-295). One functional study performed in mESCs indicated that this variant is functional (Biswas K et al. Cell Rep Methods. 2023 Nov;3(11):100628). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Apr 17, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.3310A>C (p.Thr1104Pro) variant has been reported in the published literature in individuals with a personal or family history of breast cancer (PMIDs: 36605468 (2023), 32658311 (2021), 31851867 (2020)), and also observed in reportedly healthy individuals (PMIDs: 32658311 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has been shown to have neutral effects on DNA repair-associated cell survival in a drug sensitivity assay (PMID: 37922907 (2023)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000037 (4/108720 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 12, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.3310A>C; p.Thr1104Pro variant (rs80358577), also known as 3538A>C, is reported in the literature in at least one individual with a family history of breast cancer (DE Silva 2011). A different variant at this codon (c.3311C>G; p.Thr1104Arg) has been reported in an individual with ovarian cancer (Santonocito 2017). The p.Thr1104Pro variant is reported in ClinVar (Variation ID: 51448), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1104 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show no change in binding to the APRIN protein (Brough 2012). Due to limited information, the clinical significance of the p.Thr1104Pro variant is uncertain at this time. References: Brough R et al. APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer. EMBO J. 2012 Mar 7;31(5):1160-76. DE Silva S et al. Novel sequence variants and common recurrent polymorphisms of BRCA2 in Sri Lankan breast cancer patients and a family with BRCA1 mutations. Exp Ther Med. 2011 Nov;2(6):1163-1170. Santonocito C et al. Identification of twenty-nine novel germline unclassified variants of BRCA1 and BRCA2 genes in 1400 Italian individuals. Breast. 2017 Dec;36:74-78. -

not specified Uncertain:1 Benign:1

Mar 21, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.3310A>C (p.Thr1104Pro) results in a non-conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 235988 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3310A>C has been reported in the literature in at-least one individual with breast cancer in whom a co-occurrence with another pathogenic variant was reported (BRCA1 c.5289delG, p.Leu1764fsX1), providing supporting evidence for a benign role (example, DeSilva_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, all patients with c.3310A>C, reported in BIC (n=4) and UMD (n=3) also carry another VUS, BRCA2 c.3503T>A (M1168K), suggesting an "in cis" phase for these two variants. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, Brough_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Oct 19, 2023

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Cold spot variant outside of functional domains (ClinGen ENIGMA BRCA1/2 rules) in silico prediction benign (BayesDel no AF-0.0862), splice AI no impact (0.0); BP1_strong. According to the ACMG standard criteria we chose this criterium: BP1 (strong benign): Cold spot variant outside of functional domains (ClinGen ENIGMA BRCA1/2 rules) in silico prediction benign (BayesDel no AF-0.0862), splice AI no impact (0.0); BP1_strong -

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1104 of the BRCA2 protein (p.Thr1104Pro). This variant is present in population databases (rs80358577, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 22977638, 31851867). This variant is also known as 3538A>C. ClinVar contains an entry for this variant (Variation ID: 51448). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

BRCA2-related cancer predisposition Uncertain:1

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with proline at codon 1104 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 1 individual affected with bilateral breast cancer, 1 individual affected with breast or ovarian cancer, and 2 unaffected individuals (DOI: 10.5603/OCP.2020.0026, 10.1515/tjb-2019-0424, PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008063). This variant has been identified in 4/235948 chromosomes 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.47
MutPred		0.24		Gain of catalytic residue at T1104 (P = 0.0436);Gain of catalytic residue at T1104 (P = 0.0436);
MVP		0.93
MPC		0.18
ClinPred		0.98	D
GERP RS		5.8
gMVP		0.66

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: rs80358577; hg19: chr13-32911802;