rs80358755

Positions:

• chr13-32339667-G-A
• chr13-32339667-G-C
• chr13-32339667-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.5312G>A​(p.Gly1771Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,612,280 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:32 O:1
• Conservation: PhyloP100: -0.530

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029400349).
• BP6: Variant 13-32339667-G-A is Benign according to our data. Variant chr13-32339667-G-A is described in ClinVar as [Benign]. Clinvar id is 37958.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339667-G-A is described in Lovd as [Benign]. Variant chr13-32339667-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00034 (497/1460130) while in subpopulation MID AF= 0.00886 (51/5756). AF 95% confidence interval is 0.00692. There are 2 homozygotes in gnomad4_exome. There are 241 alleles in male gnomad4_exome subpopulation. Median coverage is 45. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5312G>A	p.Gly1771Asp	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5312G>A	p.Gly1771Asp	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152032 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250488 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135596

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000424

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000340 AC: 497 AN: 1460130 Hom.: 2 Cov.: 45 AF XY: 0.000332 AC XY: 241 AN XY: 726452

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74400

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000453 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:32 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:9 Other:1

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 16, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000153 -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2015	- -

not specified Uncertain:1 Benign:9

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 18, 2018	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Gly1771Asp variant was identified in 6 of 1934 proband chromosomes from individuals with breast cancer, ovarian cancer or prostate cancer and was not detected in 100 control chromosomes evaluated (Edwards 2003, Hadjisavvas 2003, Hondow 2011, Kauff 2002, Thirthagiri 2008, Toh 2008). The variant was listed in dbSNP (ID: rs80358755) “With probable-non-pathogenic allele” with a minor allele frequency of 0.0005 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (with a frequency of 0.0006 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in HGMD, LOVD, the BIC database (43X with no clinical importance, 1X with unknown clinical importance), and in UMD (25X as a neutral variant). In UMD the variant was twice listed co-occur with a pathogenic variant in BRCA1 or BRCA2 (BRCA2 c.759 759delinsACA (p.Ser253ArgfsX24) and BRCA1 c.IVS5+3A>G (c.212+3A>G)), increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein (though this information is not predictive enough to rule out pathogenicity), and two in silico studies using multifactorial likelihood-ratio models predict the variant to be neutral or of no clinical significance (Easton 2007, Lindor 2012). Furthermore, the p.Gly1771 residue is not conserved in mammals and lower organisms, and the variant amino acid aspartic acid (Asp) is present in rat and mouse, further increasing the likelihood that this variant is not clinically important. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: 7 labs classify as LB/Ben; ExAC: 0.1% (6/11554) Latino chromosomes -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

Hereditary breast ovarian cancer syndrome Benign:5

Likely benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2015	Variant Summary: The variant of interst causes a missense change in a non-conserved position with 3/5 in silico programs predicting a "benign" outcome. The variant of interest has an observed allele frequency of 41/121940 (1/2976) including 1 homozygous occurrence. Functional analysis through the use of allelic imbalance implicated the variant does not affect splicing (Caux-Moncoutier_2009). The variant of interest has been reported in multiple affected individuals, however, it has shown lack of co-segregation within one family with an affected individual not carrying the variant of interest (Carvallone_2010). In addition, the variant of interest was reported to co-occur with another potentially pathogenic BRCA2 variant, c.759_759delinsACA and a potentially pathogenic BRCA1 variant, c.212+3A>G. Furthermore, multiple reputable databases/laboratories (ARUP, UMD, SCRP, GeneDx and Ambry Genetics) and publications (Lindor_2012, Easton_2007, and Cunningham_2014) classify the variant as "likely benign/benign/polymorphism." Therefore, taken all together, the variant of interest is classified as benign. -

not provided Benign:4

Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	BRCA2: BP4, BS3:Supporting, BS1 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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	curation	Sema4, Sema4	Sep 28, 2020	- -

Fanconi anemia complementation group D1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.6
DANN	Benign	0.72
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.14
Sift	Benign	0.43	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.22
MVP		0.77
MPC		0.023
ClinPred		0.0040	T
GERP RS		-0.34
gMVP		0.13

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: rs80358755; hg19: chr13-32913804; COSMIC: COSV99061739;