17-43067609-T-C

Variant names:

• chr17-43067609-T-C
• rs80356853
• NM_007294.4:c.5073A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID:30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003191/MONDO:0011450/092

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 2.31
• Publications: 11 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5073A>G	p.Thr1691Thr	splice_region_variant, synonymous_variant	Exon 16 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5073A>G	p.Thr1691Thr	splice_region_variant, synonymous_variant	Exon 16 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455088 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105864

Other (OTH) AF: 0.00 AC: 0 AN: 60156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Mar 14, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Uncertain:1

Jun 11, 2024

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID: 30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3). -

not provided Uncertain:1

Jul 09, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.5073A>G at the DNA level. Although the variant is silent at the coding level, preserving a Threonine at codon 1691, multiple in silico models predict this variant to negatively impact the nearby natural splice donor site, and to possibly cause abnormal gene splicing. This variant, also known as BRCA1 c.5192A>G by alternate nomenclature, was shown to exhibit loss of function when studied by a transcription activation assay (Carvalho 2002). BRCA1 c.5073A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, an adenine (A) at base 5073, is well conserved across mammals. Based on currently available information, it is unclear whether BRCA1 c.5073A>G is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5073A>G variant (also known as p.T1691T), located in coding exon 15, results from an A to G substitution at nucleotide position 5073 of the BRCA1 gene. This nucleotide substitution does not change the amino acid at codon 1691. However, this change occurs in the second to last base pair of coding exon 15, which gives it potential to have some effect on normal mRNA splicing. This alteration (designated as 5192A>G) exhibited loss of function when studied by a transcriptional activation assay in yeast, but was also reported as functional in a high throughput, genome editing, haploid cell survival assay (Carvalho MA et al. Cancer Biol.Ther. 2002 Sep;1(5):502-8; Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, however, direct evidence is insufficient at this time (Ambry internal data). A different alteration at this location, c.5073A>T, also predicted to weaken the native donor site, has been reported as having a splicing impact in the literature, producing two aberrant transcripts, one resulting in skipping of coding exon 15, and one with a partial inclusion of intron 15 (Coppa A et al. Cancer Med, 2018 01;7:46-55). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1691 of the BRCA1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55374). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 30209399; Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Fanconi anemia, complementation group S Uncertain:1

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

A known synonymous variant, c. 5073A>G p.(Thr1691=) in exon 16 of BRCA1 (NM_007294.4) was identified in the proband in heterozygous state. This variant is inherited from his mother. This variant is reported in one individual in a heterozygous state in the gnomAD (v4.1.0) population database. It is not reported in heterozygous state in our in-house database of 3204 exomes. This variant has been reported in a heterozygous state in an individual with hereditary breast and ovarian carcinoma (Minucci et al., 2018). This variant is reported in ClinVar database as a variant of uncertain significance in five independent submissions (ClinVar ID - 55374). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.71		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356853; hg19: chr17-41219626;