rs55854959

Positions:

• chr13-32330979-G-A
• chr13-32330979-G-C
• chr13-32330979-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):​c.742G>A​(p.Ala248Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:6 O:1
• Conservation: PhyloP100: 0.207

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045834124).
• BP6: Variant 13-32330979-G-A is Benign according to our data. Variant chr13-32330979-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52326.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6, not_provided=1, Benign=2}. Variant chr13-32330979-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.742G>A	p.Ala248Thr	missense_variant	9/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.742G>A	p.Ala248Thr	missense_variant	9/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.373G>A	p.Ala125Thr	missense_variant	9/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.742G>A		non_coding_transcript_exon_variant	8/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

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: 0.0000239 AC: 6 AN: 250956 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135662

Gnomad AFR exome AF: 0.000308

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: 0.0000274 AC: 40 AN: 1461480 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727070

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74410

Gnomad4 AFR AF: 0.000433

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: 0.0000614 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 31, 2023	The BRCA2 c.742G>A (p.Ala248Thr) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with a personal history of breast cancer (PMID: 15744044). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Nov 13, 1997	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2022	Variant summary: BRCA2 c.742G>A (p.Ala248Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 298566 control chromosomes (gnomAD, Bodian_2014, Fackenthal_2005, Momozawa_2018), predominantly at a frequency of 0.00031 within the African or African-American 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.742G>A has been reported in the literature in individuals affected with breast cancer (example: Gao_2000, Haffty_2006, Maxwell_2015, Dorling_2021), however, it was also found in healthy controls (example: Bodian_2014, Momozawa_2018, Dorling_2021, FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. This variant was found co-occurring with another pathogenic BRCA2 variant via internal testing (BRCA2 c.5164_5165delAG, p.Ser1722fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2021	This sequence change has been previously described in individuals with breast cancer and reportedly unaffected individuals (PMIDs: 15744044, 12491487, 30287823, 15983021, 22034289, 24728327). This sequence change has been described in the gnomAD database with a frequency of 0.028% in the African subpopulation (dbSNP rs55854959). The p.Ala248Thr change affects a poorly conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. The p.Ala248Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala248Thr change remains unknown at this time. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2023	Observed in individuals with breast cancer, but also in unaffected controls (Olopade et al., 2003; Fackenthal et al., 2005; Haffty et al., 2006; Maxwell et al., 2015; Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 970G>A; This variant is associated with the following publications: (PMID: 15744044, 12491487, 26773734, 28814288, 30287823, 15983021, 22034289, 24728327, 27300552, 25637381, 25503501, 11030417, 24504028, 33471991, 33233347) -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2019	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, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2016	- -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Ala248Thr variant was identified in 5 of 14324 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and was identified in 1 of 1510 chromosomes from healthy individuals (Amendola 2015, Fackenthal 2005, Fackenthal 2012, Haffty 2005). The variant was also identified in dbSNP (ID: rs55854959) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, BIC and three other clinical laboratories), Cosmic (2x), MutDB, LOVD 3.0 (2x), UMD-LSDB (3x as unclassified variant), and BIC (4x as unknown significance). The variant was not identified in the COGR, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 9 of 276698 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23984 chromosomes (freq: 0.0003) and European in 1 of 126390 chromosomes (freq: 0.000008), but not in the “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala248 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 02, 2020

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

BRCA2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

The BRCA2 c.742G>A variant is predicted to result in the amino acid substitution p.Ala248Thr. This variant has been reported in 8 heterozygous individuals within the gnomAD population database and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/52326/). This variant has been reported in a Nigerian individual with breast cancer who also had an additional intronic variant in their BRCA2 gene, however its significance was unclear (Table 1, Fackenthal et al 2005, PubMed ID: 15744044). More recent studies have identified this variant in at least one individual from the NHLBI ESP database and also classified its significance as uncertain (Amendola et al. 2015, PubMed ID: 25637381) while another identified it within a healthy, ancestrally diverse cohort (Bodian et al. 2014, PubMed ID: 24728327). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.78
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.16	T;T
Vest4		0.28
MVP		0.76
MPC		0.020
ClinPred		0.011	T
GERP RS		-0.16
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs55854959; hg19: chr13-32905116; COSMIC: COSV66463157;