13-32379412-G-T

Variant names:

• chr13-32379412-G-T
• rs28897754
• NM_000059.4:c.8850G>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS2

The NM_000059.4(BRCA2):​c.8850G>T​(p.Lys2950Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,613,836 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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. K2950L?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:28 O:1
• Conservation: PhyloP100: 2.06

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 -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32379409-GA-GCT is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.023308098).
• BP6: Variant 13-32379412-G-T is Benign according to our data. Variant chr13-32379412-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52692.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, Benign=9, Uncertain_significance=2, not_provided=1}. Variant chr13-32379412-G-T is described in Lovd as [Benign]. Variant chr13-32379412-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8850G>T	p.Lys2950Asn	missense_variant	Exon 22 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8850G>T	p.Lys2950Asn	missense_variant	Exon 22 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8481G>T	p.Lys2827Asn	missense_variant	Exon 22 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*908G>T		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*908G>T		3_prime_UTR_variant	Exon 21 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000738 AC: 185 AN: 250752 Hom.: 0 AF XY: 0.000634 AC XY: 86 AN XY: 135552

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000820 AC: 1199 AN: 1461516 Hom.: 0 Cov.: 31 AF XY: 0.000816 AC XY: 593 AN XY: 727044

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000958

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74496

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00109

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:28 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:8

Feb 25, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BA1(Stand alone)+BS3(Strong)+BP4(Supporting)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Mar 02, 2020

BRCAlab, Lund University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2014

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP3,BP1,BP6. -

not specified Uncertain:1 Benign:7 Other:1

Mar 15, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys2950Asn variant was identified in 17 of 11804 proband chromosomes (frequency: 0.001) from individuals or families with Breast, Ovarian and Prostate Cancers, and was present in 2 of 1166 control chromosomes (frequency: 0.002) from healthy individuals (Diez_2003_12955716, Spurdle_2008_18375895, Akbari_2011_21965345, Beristain_2007_17262179, Borg_2010_20104584, Edwards_2003_12474142, Esteban-Cardenosa_2004_14684619, Gayther_2000_10969800, Miramar_2008_18176857, Romano_2007, Schoumacher_2001_11400546, Soegaard_2008_18559594, Soegaard_2008_18559594, Cavallone_2010_20694749). The variant was also identified in dbSNP (ID: rs28897754) “With Likely benign allele”, with a minor allele frequency of 0.0012(1000 Genomes Project) and with an average heterozygosity score with standard error of 0.002+/-0.035, increasing the likelihood that this is a benign variant. In NHLBI Exome Sequencing Project (Exome Variant Server) the variant was identified in 7 of 8600 European Americans and was not found in African Americans. In Exome Aggregation Consortium (ExAC) database the variant was identified in 21 of 11524 Latino alleles, 54 of 66378 European (Non Finnish) alleles, 5 of 6610 of Europeans (Finnish) alleles, increasing the likelihood this variant is a low frequency benign polymorphism in certain populations of origin. The variant was identified in the ClinVar database with conflicting classifications. It was classified as a benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), Ambry Genetics, Counsyl and Invitae; as likely benign by Emory Genetics, CHEO and GeneDX; as uncertain significance by BIC. The variant was identified in the BIC database (111X with unknown clinical importance), and in UMD (78X as a neutral variant). In UMD the variant was identified with co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1:c.1483_1498del (p.Glu495IlefsX3), c.IVS5+2T>C, c.34C>T (p.Gln12X), c.3841C>T (p.Gln1281X), c.70T>C (p.Cys24Arg), c.IVS5+3A>G (c.212+3A>G); BRCA2: c.8904delC (p.Val2969CysfsX7), c.7007G>A (p.Arg2336His)), increasing the likelihood that the p.Lys2950Asn variant does not have clinical significance. The p.Lys2950 residue is conserved across mammals and lower organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the Asn (asparagine) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Dec 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Lys2950Asn va riant in BRCA2 has been reported in at least 1 individual with BRCA2-associated cancer (Blay 2013). This variant has also been identified in 0.2% (21/11524) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs28897754). Computational prediction tools and conservation analysis suggest that the p.Lys2950Asn variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Lys2950Asn variant is uncertain, its f requency suggests that it is more likely to be benign. -

Mar 17, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Benign:4

Oct 23, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 07, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2016

Vantari Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4, BS2 -

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Uncertain:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breast and/or ovarian cancer Benign:1

May 17, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

Apr 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.0088
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-0.35	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.38
MutPred		0.69		Loss of ubiquitination at K2950 (P = 0.0051);Loss of ubiquitination at K2950 (P = 0.0051);
MVP		0.86
MPC		0.17
ClinPred		0.051	T
GERP RS		1.8
gMVP		0.49

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: rs28897754; hg19: chr13-32953549; COSMIC: COSV66455693; COSMIC: COSV66455693;