17-43063883-T-A

Variant names:

• chr17-43063883-T-A
• rs80357222
• NM_007294.4:c.5143A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5143A>T​(p.Ser1715Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1715T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 3.39
• Publications: 35 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 67 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063882-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55416.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 17-43063883-T-A is Pathogenic according to our data. Variant chr17-43063883-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. 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
	BRCA1	NM_007294.4	MANE Select	c.5143A>T	p.Ser1715Cys	missense	Exon 17 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5209A>T	p.Ser1737Cys	missense	Exon 18 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5209A>T	p.Ser1737Cys	missense	Exon 18 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5143A>T	p.Ser1715Cys	missense	Exon 17 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5206A>T	p.Ser1736Cys	missense	Exon 18 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5143A>T	p.Ser1715Cys	missense	Exon 17 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.5143A>T (p.Ser1715Cys) variant has been reported in the published literature in families affected with a hereditary breast/ovarian cancer (PMID: 16267036 (2005)). This variant shows functional defects in transcriptional activation as well as DNA damage response and repair (PMIDs: 20516115 (2010), 25748678 (2015), 28781887 (2016), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Mar 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in an individual with ovarian cancer (PMID: 36169650); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5262A>T; Published functional studies demonstrate a damaging effect: impaired homology-directed repair and transcriptional activity, and compromised protein folding and stability (PMID: 20516115, 20378548, 28781887, 30209399, 30765603, 35665744); This variant is associated with the following publications: (PMID: 20516115, 20378548, 15235020, 17305420, 12955719, 30209399, 30765603, 28781887, 35665744, 25748678, 25348405, 36169650)

Hereditary breast ovarian cancer syndrome Pathogenic:2

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1715 of the BRCA1 protein (p.Ser1715Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 36169650). ClinVar contains an entry for this variant (Variation ID: 55415). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20378548, 20516115, 24845084, 25748678, 30209399, 30765603). This variant disrupts the p.Ser1715 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 22856468). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Dec 15, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5143A>T (p.Ser1715Cys) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant has been reported to have a destabilizing effect on the BRCA1 protein (Rowling_2010). The variant was absent in 251300 control chromosomes. c.5143A>T has been reported in the literature in at-least one individual affected with and/or undergoing testing for Hereditary Breast And Ovarian Cancer (Judkins_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. However, a different missense variant located at the same codon, namely p.Ser1715Asn has been reported to segregate with breast and ovarian cancer in an extended family pedigree (Campbell_2013) suggesting an impact on protein function. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of HDR capacity (Findlay_2018) and an inability to form ionization-radiation induced foci (IRIS) despite a retained ability to recruit Rad51 to sites of double stranded breaks (DSB) (Gaboriau_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely pathogenic and one classified the variant as uncertain significance. All submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

May 02, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1715C variant (also known as c.5143A>T), located in coding exon 16 of the BRCA1 gene, results from an A to T substitution at nucleotide position 5143. The serine at codon 1715 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration impacts a highly-conserved residue within the N-terminal BRCT functional domain of BRCA1 and has been shown to result in significantly reduced protein function in several protein functional assays (Rowling P et al. J Biol Chem. 2010 Jun 25;285(26):20080-7; Lee M et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Findlay GM et al. Nature 2018 10;562(7726):217-222). Of note, this alteration is also referred to as 5262A>T in published literature. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Jun 20, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.83
MVP		0.96
MPC		0.42
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.84
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80357222; hg19: chr17-41215900;