chr17-43124086-G-A

Position:

• chr17-43124086-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000357654.9(BRCA1):​c.11C>T​(p.Ser4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 2.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 11 uncertain in ENST00000357654.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40271246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.11C>T	p.Ser4Phe	missense_variant	2/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.11C>T	p.Ser4Phe	missense_variant	2/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460762 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 05, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2019

The p.S4F variant (also known as c.11C>T), located in coding exon 1 of the BRCA1 gene, results from a C to T substitution at nucleotide position 11. The serine at codon 4 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In one study, functional analysis of this variant using a cisplatin sensitivity assay were inconclusive as repeat experiments showed discordant results (Bouwman P, Cancer Discov 2013 Oct; 3(10):1142-55). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2023

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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 4 of the BRCA1 protein (p.Ser4Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 26283626). ClinVar contains an entry for this variant (Variation ID: 186697). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.;.;.;T;.;T;T;.;T;T;.;T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	L;L;L;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.87	D;D;D;D;D;D;D;D;D;D;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	N;N;N;D;D;D;N;.;N;N;N;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;.;D;.;D;.;D;.;.;.
Polyphen		1.0, 0.94, 0.97	.;D;.;.;P;.;D;.;.;.;.;.;.;.
Vest4		0.43
MutPred		0.36		Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);
MVP		0.88
MPC		0.37
ClinPred		0.82	D
GERP RS		2.8
Varity_R		0.29
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs786203152; hg19: chr17-41276103;