rs55847618

chr13-32398283-A-Gchr13-32398283-A-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.9770A>G(p.Lys3257Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. K3257I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:9
• Conservation: PhyloP100: -0.0320

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01681292).
• BP6: Variant 13-32398283-A-G is Benign according to our data. Variant chr13-32398283-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=5, Benign=1}. Variant chr13-32398283-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9770A>G	p.Lys3257Arg	missense_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9770A>G	p.Lys3257Arg	missense_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

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: 0.000478

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251422 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135886

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727234

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.0000447

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74484

Gnomad4 AFR AF: 0.000698

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: 0.000473

Alfa AF: 0.0000433 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 18, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 12, 2009	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2021	The p.Lys3257Arg variant in BRCA2 is classified as likely benign because it has been identified in 0.072% (18/24972) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: BRCA2 c.9770A>G (p.Lys3257Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251422 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database (v2.1.1, Exomes cohort). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.9770A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, however, without strong evidence for causality (e.g., Fackenthal_2012, Pal_2013). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.4712_4713delAG, p.Glu1571fsX3; BRCA2 c.6155dupC, p.Ser2053fsX7; BRCA2 c.2186_2187delTC, p.Ile729LysfsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters (evaluation after 2014) have cited the variant as either VUS (n=5) or benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2021	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2016	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2019	This variant is associated with the following publications: (PMID: 10923033, 26580448, 24817641, 23555315, 23320992, 22034289, 9971877) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 26, 2020	The BRCA2 c.9770A>G; p.Lys3257Arg variant (rs55847618), also known as A9998G, is reported in the literature in individuals affected with breast cancer (Fackenthal 2012, Pal 2013). This variant is reported in ClinVar (Variation ID: 52897), and is found in the African population with an allele frequency of 0.07% (18/24972 alleles) in the Genome Aggregation Database. The lysine at codon 3257 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Lys3257Arg variant is uncertain at this time. REFERENCES Fackenthal JD et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. Pal T et al. Early onset breast cancer in a registry-based sample of African-american women: BRCA mutation prevalence, and other personal and system-level clinical characteristics. Breast J. 2013 Mar-Apr;19(2):189-92. -

BRCA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	10
Dann	Uncertain	0.99
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.050	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.17
Sift	Benign	0.45	T;T
Sift4G	Benign	0.56	T;T
Vest4		0.14
MVP		0.65
MPC		0.029
ClinPred		0.012	T
GERP RS		1.3
gMVP		0.17

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: rs55847618; hg19: chr13-32972420;