13-32379900-A-G

Variant names:

• chr13-32379900-A-G
• rs80359165
• NM_000059.4:c.9104A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000059.4(BRCA2):​c.9104A>G​(p.Tyr3035Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y3035S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 2.75
• Publications: 46 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 16 benign, 32 uncertain in NM_000059.4
• BP6: Variant 13-32379900-A-G is Benign according to our data. Variant chr13-32379900-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52751.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9104A>G	p.Tyr3035Cys	missense	Exon 23 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.9104A>G	p.Tyr3035Cys	missense	Exon 23 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.9053A>G	p.Tyr3018Cys	missense	Exon 23 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9104A>G	p.Tyr3035Cys	missense	Exon 23 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9104A>G	p.Tyr3035Cys	missense	Exon 23 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8735A>G	p.Tyr2912Cys	missense	Exon 23 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249232 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461382 Hom.: 0 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000909 AC: 101 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74400

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000183 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Sep 13, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 17972171 (2008), 20104584 (2010), 28222693 (2017), 29681614 (2018), 30287823 (2018), 31837001 (2020)), and biliary tract cancer (PMID: 36243179 (2022)), as well as in healthy individuals (PMIDs: 28222693 (2017), 30287823 (2018), 31837001 (2020), 32467295 (2020)). Additionally, functional studies report this variant has a neutral effect on BRCA2 protein function (PMIDs: 35736817 (2022), 33314489 (2021), 29394989 (2018)). The frequency of this variant in the general population, 0.00025 (5/19766 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with personal or family history of breast or ovarian cancer, but also in healthy controls (Thirthagiri 2008, Borg 2010, Capanu 2011, Dodova 2015, Lai 2017, Apessos 2018, Liang 2018, Wen 2018); Published functional studies suggest no damaging effect: homology-directed repair (HDR) activity comparable to wild type (Guidugli 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21702907, 18627636, 21520273, 19043619, 20104584, 26183948, 28222693, 28993434, 29310832, 30702160, 29681614, 31131967, 29394989, 32123317, 31837001, 33314489, 29884841)

Hereditary cancer-predisposing syndrome Benign:2

Jan 28, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Tyr3035Cys variant has been identified in 3 of 4580 proband chromosomes (frequency 0.001) in individuals with breast or ovarian cancers (Borg 2010, Thirthagiri 2008); however, control chromosomes from healthy individuals were not included in these studies. This variant was reported in the BIC database 3X as a variant of unknown clinical significance, and was also reported in the HGMD, LOVD and dbSNP databases. The p.Tyr3035 residue is conserved across mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Tyr3035Cys variant may impact the protein. In addition, one functional in silico study predicts this variant to be likely deleterious (Karchin 2008). This increases the likelihood this variant may have clinical significance, however, this information is not predictive enough to assume pathogenicity and additional data is needed to support these findings. In summary, based on the above information the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance.

not specified Benign:1

Nov 14, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9104A>G (p.Tyr3035Cys) 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 allele was found at a frequency of 3.2e-05 in 281918 control chromosomes, predominantly at a frequency of 0.00022 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9104A>G has been reported in the literature in individuals affected with and/or undergoing testing for Hereditary Breast and Ovarian Cancer (e.g. Gorringe_2008, Thirthagiri_2008, Borg_2010, Hondow_2011, Lai_2017, Wen_2017, Apessos_2018, Liang_2018, Guo_2019) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (HDR) activity (Guidugli_2018, Hu_2022) and lack of sensitivity to DNA damage agents (Sullivan_2021). The following publications have been ascertained in the context of this evaluation (PMID: 29310832, 30702160, 20104584, 21520273, 25556339, 17972171, 29394989, 31837001, 29884841, 21702907, 35736817, 19043619, 28222693, 29681614, 30287823, 33314489, 18627636, 32123317, 28993434). ClinVar contains an entry for this variant (Variation ID: 52751). Based on the evidence outlined above, the variant was classified as likely benign.

Hereditary breast ovarian cancer syndrome Benign:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	0.0028	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.18	D
PhyloP100		2.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.55
MutPred		0.56		Loss of catalytic residue at P3039 (P = 0.0664)
MVP		0.91
MPC		0.17
ClinPred		0.85	D
GERP RS		4.5
gMVP		0.62
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80359165; hg19: chr13-32954037; COSMIC: COSV99061633;