rs769712441

Variant names:

• chr17-43092865-G-A
• rs769712441
• NM_007294.4:c.2666C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43092865-G-A
• chr17-43092865-G-C
• chr17-43092865-G-T

Variant summary

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

The NM_007294.4(BRCA1):​c.2666C>T​(p.Ser889Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S889Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 3.18
• Publications: 17 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2666C>T	p.Ser889Phe	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2666C>T	p.Ser889Phe	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 251042 AF XY: 0.0000147

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461666 Hom.: 0 Cov.: 53 AF XY: 0.0000124 AC XY: 9 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

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:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jun 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000026 (3/113468 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 21918853 (2012)), kidney cancer (PMID: 29684080 (2018)), and in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). In addition, this variant has been reported in the somatic state in an individual with sporadic triple negative breast cancer (PMID: 29202330 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 17, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (de Juan Jimenez 2012); Also known as 2785C>T; This variant is associated with the following publications: (PMID: 33206719, 31937788, 27767231, 21918853) -

Dec 22, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA1 c.2666C>T; p.Ser889Phe variant (rs769712441) is reported in the literature in individuals affected with breast or cancer, but without clear disease association (de Juan Jimenez 2012, Weren 2017). This variant is also reported in ClinVar (Variation ID: 186759), but is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 889 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.449). Due to limited information, the clinical significance of this variant is uncertain at this time. References: de Juan Jimenez et al. Low prevalence of BRCA1 and BRCA2 mutations in the sporadic breast cancer of Spanish population. Fam Cancer. 2012 Mar;11(1):49-56. PMID: 21918853. Weren RD et al. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. Hum Mutat. 2017 Feb;38(2):226-235. PMID: 27767231. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with phenylalanine at codon 889 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least two individuals affected with breast cancer and one individual each affected with kidney and unspecified pediatric cancer (PMID: 21918853, 29684080, 31937788; Color data) and in a breast cancer case-control meta-analysis in 2/53461 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006398). This variant has been identified in 3/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S889F variant (also known as c.2666C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2666. The serine at codon 889 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been reported in multiple breast and ovarian cancer cohorts (de Juan Jim&eacute;nez I et al. Fam Cancer, 2012 Mar;11:49-56; Grigore LG et al. Curr Issues Mol Biol, 2024 May;46:4630-4645; Hovland HN et al. Fam Cancer, 2022 Oct;21:389-398). This alteration was identified in a cohort of pediatric patients referred for genetic testing for diverse clinical indications (Chirita-Emandi A et al. Sci Rep. 2020 01;10:223). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). Of note, this alteration is also known as c.2785C>T in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 889 of the BRCA1 protein (p.Ser889Phe). This variant is present in population databases (rs769712441, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer or suspected hereditary cancer (PMID: 21918853, 34981296). This variant is also known as 2785C>T. ClinVar contains an entry for this variant (Variation ID: 186759). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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. -

Familial pancreatic carcinoma Benign:1

Feb 05, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Pathogenic	3.0	M;M;.;.
PhyloP100		3.2
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.99	D;.;.;P
Vest4		0.42
MutPred		0.40		Loss of phosphorylation at S889 (P = 0.0418);Loss of phosphorylation at S889 (P = 0.0418);.;Loss of phosphorylation at S889 (P = 0.0418);
MVP		0.81
MPC		0.35
ClinPred		0.95	D
GERP RS		3.0
Varity_R		0.28
gMVP		0.31
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs769712441; hg19: chr17-41244882; COSMIC: COSV106433631;