17-43063882-C-T

Variant names:

• chr17-43063882-C-T
• rs45444999
• NM_007294.4:c.5144G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5144G>A​(p.Ser1715Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:2
• Conservation: PhyloP100: 4.86
• Publications: 28 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 14 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 chr17-43063883-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55414.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 17-43063882-C-T is Pathogenic according to our data. 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.

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.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5210G>A	p.Ser1737Asn	missense	Exon 18 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5210G>A	p.Ser1737Asn	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.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5207G>A	p.Ser1736Asn	missense	Exon 18 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5144G>A	p.Ser1715Asn	missense	Exon 17 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460404 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726612

⚠️ 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: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110700

Other (OTH) AF: 0.00 AC: 0 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

May 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 1715 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay, transcription activation assays, homology-directed DNA repair assay, a nuclear localization assay, and other ancillary assays (PMID: 11157798, 20516115, 29884841, 30209399, 30257991). This variant has been reported in affected members of two hereditary breast and ovarian cancer families (PMID: 12955716, 12955719, 22856468) and reported in additional suspected hereditary breast and ovarian cancer families (PMID: 34597585). This variant is reported to segregate with breast and/or ovarian cancer (PMID: 12955716, 12955719, 22856468), and two multifactorial analysis have reported likelihood ratios for pathogenicity based on segregation of 57.86 and 167.97 (PMID: 31131967, 34597585). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Dec 15, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1715N pathogenic mutation (also known as c.5144G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5144. The serine at codon 1715 is replaced by asparagine, an amino acid with highly similar properties. This alteration was found to segregate with both breast and ovarian cancer in multiple individuals from a large British family (Campbell J et al. Clin. Genet., 2013 May;83:485-7) and has been identified in a family with multiple cases of breast cancer from a cohort of 83 Spanish breast and/or ovarian cancer families (D&iacute;ez O et al. Int. J. Cancer, 1999 Nov;83:465-9). Numerous functional studies have shown that this variant is functionally defective including in homology directed repair, haploid cell survival, yeast growth retardation, transcriptional activation assays, binding activity and specificity, protease sensitivity, and overall stability (Vallon-Christersson J et al. Hum. Mol. Genet., 2001 Feb;10:353-60; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Findlay GM et al. Nature, 2018 10;562:217-222). This variant was determined to be pathogenic in a multifactorial analysis which combined family history, pathology, and co-segregation data (Parsons M. et al. Hum. Mutat. 2019 09;40(9):1557-1578). Internal structural analysis determined that this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Mar 05, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2_Supporting, PP4_VeryStrong c.5144G>A, located in exon 17 of the BRCA1 gene, is found in a (potentially) clinically important functional domain and is predicted to result in the substitution of Ser by Asn at codon 1715, p.(Ser1715Asn). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The BayesDel_noAF predictor score for this variant (-0,047) suggests that it does not affect the protein function but the SpliceAI algorithm is indeterminate regarding the impact on splicing (SpliceAI-AcceptorGain score: 0.11). It has been reported by three calibrated studies to affect protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). RNA experimental analysis indicated no impact on splicing (PMIDs: 12955719, 21673748). Moreover, published clinical data for a multifactorial likelihood analysis (PMID: 31131967) showed a combined LR indicative of very strong evidence towards pathogenicity (LR 1016.9) (PP4_VeryStrong). In addition, the variant was also identified in the following databases: BRCA Exchange (Pathogenic: IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999494), ClinVar (2x uncertain significance, 2x likely pathogenic, 4x pathogenic) and LOVD (6x NA). Based on currently available information, the variant c.5144G>A should be considered a pathogenic variant.

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

Sep 18, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999494

not provided Pathogenic:2 Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 27, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast and/or ovarian cancer, and segregates with disease in one large family (Dez 1999, Campbell and Speevak 2013); Published functional studies demonstrate a damaging effect: impaired transciptional activity, structural stability, binding activity and specificity, protease sensitivity, cell survival, and homology-directed repair activity (Vallon-Christersson 2001, Lee 2010, Woods 2016, Findlay 2018, Fernandes 2019, Petitalot 2019, Lyra 2021); Multifactorial likelihood analyses suggest this variant is pathogenic (Parsons 2019, Caputo 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5263G>A; This variant is associated with the following publications: (PMID: 17305420, 11157798, 25782689, 30209399, 30765603, 20516115, 33087888, 28781887, 31131967, 30257991, 10508480, 34597585, 21447777, 22856468)

Hereditary breast ovarian cancer syndrome Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1715 of the BRCA1 protein (p.Ser1715Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10508480, 22856468). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55416). 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 have shown that this missense change affects BRCA1 function (PMID: 11157798, 20516115, 28781887, 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, 20516115, 29176636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Benign	0.059	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.43	B
Vest4		0.81
MVP		0.93
MPC		0.33
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.83
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
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: rs45444999; hg19: chr17-41215899; COSMIC: COSV107367492;