17-43047685-C-A

Variant names:

• chr17-43047685-C-A
• rs28897698
• NM_007294.4:c.5425G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_007294.4(BRCA1):​c.5425G>T​(p.Val1809Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1809A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 1.17

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 17 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 chr17-43047684-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 825725.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 17-43047685-C-A is Pathogenic according to our data. Variant chr17-43047685-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55573.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4}. Variant chr17-43047685-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5425G>T	p.Val1809Phe	missense_variant	Exon 22 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5425G>T	p.Val1809Phe	missense_variant	Exon 22 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Oct 28, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: decreased transcriptional activity, peptide binding activity and specificity (Williams 2004, Phelan 2005, Fernandes 2019, Drikos 2021); Observed in individuals with breast and ovarian cancer, segregating with disease in one family (Phelan 2005, Thomassen 2008, Fostira 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed in large population cohorts (Lek et al., 2016); Also known as 5544G>T; This variant is associated with the following publications: (PMID: 16528612, 31131967, 15689452, 17305420, 19452558, 21447777, 15172985, 20516115, 14534301, 15133503, 18465347, 15385441, 20167696, 17719744, 28781887, 30765603, 31300551, 32123317, 32546644, 34083286) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with phenylalanine at codon 1809 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 in homology-directed repair, transcription activation and cisplatin and olaparib sensitivity assays and may compromise protein stability, protein localization, and protein-protein interaction (PMID: 14534301, 15133503, 15689452, 16528612, 19452558, 20516115, 28781887, 32546644, 34083286). This variant has been observed in multiple individuals affected with breast cancer from at least three unrelated families (PMID: 15689452, 18465347, 31300551, 33471991; Leiden Open Variation Database DB-ID BRCA1_000474), including an individual affected with breast and endometrial cancer (PMID: 31300551) and the co-segregation with four affected members of a hereditary breast cancer family (PMID: 15689452). 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 Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1809F variant (also known as c.5425G>T), located in coding exon 21 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5425. The valine at codon 1809 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been identified in breast cancer cohorts and has been shown to segregate with disease in one family (Phelan CM et al. J Med Genet, 2005 Feb;42:138-46; Thomassen M et al. Acta Oncol, 2008;47:772-7; Fostira F et al. J Med Genet 2020 Jan;57(1):53-61). Protein functional studies have demonstrated this variant to have a deleterious impact on function (Bouwman P et al. Clin Cancer Res, 2020 Sep;26:4559-4568; Woods NT et al. NPJ Genom Med, 2016 Mar;1:16001; Fernandes VC et al. J Biol Chem, 2019 Apr;294:5980-5992; Lee MS et al. Cancer Res, 2010 Jun;70:4880-90; Drikos I et al. Anticancer Res, 2021 Jun;41:2953-2962). This alteration was inconclusive in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology and case-control data (Parsons MT et al. Hum Mutat 2019 Sep;40(9):1557-1578). Of note, this alteration is also referred to as c.5544G>T in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Jan 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with phenylalanine at codon 1809 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant impacts BRCA1 in homology-directed repair, transcription activation and cisplatin and olaparib sensitivity assays and may compromise protein stability, protein localization, and protein-protein interaction (PMID: 14534301, 15133503, 15689452, 16528612, 19452558, 20516115, 28781887, 32546644, 34083286). This variant has been observed in multiple individuals affected with breast cancer from at least three unrelated families (PMID: 15689452, 18465347, 31300551, 33471991; Leiden Open Variation Database DB-ID BRCA1_000474), including an individual affected with breast and endometrial cancer (PMID: 31300551) and the co-segregation with four affected members of a hereditary breast cancer family (PMID: 15689452). 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 Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1809 of the BRCA1 protein (p.Val1809Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast, ovarian and/or endometrial cancer (PMID: 15689452, 18465347, 31300551). It has also been observed to segregate with disease in related individuals. This variant is also known as 5544G>T. ClinVar contains an entry for this variant (Variation ID: 55573). 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%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15689452, 19452558, 20516115, 28781887, 32546644, 34083286). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.23	D
PROVEAN	Benign	0.42	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.65
MutPred		0.49		Gain of sheet (P = 0.0266);
MVP		0.81
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28897698; hg19: chr17-41199702;