chr13-32370498-A-G

Variant names:

• chr13-32370498-A-G
• rs80359089
• NM_000059.4:c.8428A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.8428A>G​(p.Ser2810Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S2810N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 3.12
• Publications: 11 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 29 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.24664983).
• BP6: Variant 13-32370498-A-G is Benign according to our data. Variant chr13-32370498-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52584.

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.8428A>G	p.Ser2810Gly	missense	Exon 19 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8428A>G	p.Ser2810Gly	missense	Exon 19 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8428A>G	p.Ser2810Gly	missense	Exon 19 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.8428A>G	p.Ser2810Gly	missense	Exon 19 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8428A>G	p.Ser2810Gly	missense	Exon 19 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8059A>G	p.Ser2687Gly	missense	Exon 19 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251384 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Mar 22, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA2 c.8428A>G at the cDNA level, p.Ser2810Gly (S2810G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8656A>G. This variant has not, to our knowledge, been published in the literature as a germline variant; however it has been reported as a somatic variant in a lung tumor (Hovelson 2015). BRCA2 Ser2810Gly was not observed in large population cohorts (Lek 2016). BRCA2 Ser2810Gly is located in the DNA binding domain (Yang 2002). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Ser2810Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.

May 01, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 20, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Feb 13, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 06, 2019

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 and/or ovarian cancer Uncertain:1

Apr 16, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

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 BRCA2, p.Ser2810Gly variant was identified in the literature (Karchin 2008) and dbSNP database “With Uncertain significance allele.” This variant also was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 individual of European (Non-Finnish) descent. The variant was not found in populations of South Asians, European (Non-Finnish), East Asian, African, Latino, and other individuals. The variant was also identified in Clinvar database and classified as a variant of uncertain significance by BIC and Ambry Genetics; no classification was provided by Invitae. The p.Ser2810Gly variant was identified in BRCA Share UMD Database 1X and classified as unknown. In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (BRCA1: c.3481_3491del, p.Glu1161PhefsX3), increasing the likelihood that the p.Ser2810Gly variant does not have clinical significance. The variant was identified 1X in BIC database with unknown clinical importance and 1X in LOVD as neutral. The p.Ser2810 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% chance that the variant creates the loss of a cryptic 3’ acceptor splice site. However, this information is not predictive enough to assume pathogenicity. In addition, likelihood ratio analysis predicted the variant does not impair protein function and was determined neutral (Karchin 2008). 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.

not specified Benign:1

Nov 26, 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.8428A>G (p.Ser2810Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8428A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found this variant to have a neutral impact in an HDR assay (example, Hart_2019, Richardson_2021). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). ClinVar contains an entry for this variant (Variation ID: 52584). Based on the evidence outlined above, the variant was classified as likely benign.

Hereditary breast ovarian cancer syndrome Benign:1

Dec 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	Benign	0.074
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.69	T
PhyloP100		3.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.32
Sift	Benign	0.055	T
Sift4G	Uncertain	0.046	D
Vest4		0.49
MutPred		0.33		Loss of stability (P = 0.032)
MVP		0.85
MPC		0.16
ClinPred		0.70	D
GERP RS		2.7
gMVP		0.48
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80359089; hg19: chr13-32944635; COSMIC: COSV66454349;