17-43070963-A-G

Position:

• chr17-43070963-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.4951T>C​(p.Ser1651Pro) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 O:1
• Conservation: PhyloP100: 5.03

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 6 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4951T>C	p.Ser1651Pro	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4951T>C	p.Ser1651Pro	missense_variant	15/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2017	Variant summary: The BRCA1 c.4951T>C (p.Ser1651Pro) variant located in the BRCT domain (InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict damaging outcome for this variant and structural analysis is also consistent with such outcome (Karchin_2007). This variant is absent in 121406 control chromosomes from ExAC and has also not been reported in affected individuals in the literature to our knowledge. One clinical diagnostic laboratory has classified this variant as "uncertain significance," without evidence to independently evaluate. The variant was assessed for its ability to functionally complement BRCA1-deficient mouse embryonic stem cells, however, results for this variant were ambivalent (Bouwman_2013). Another missense change at the same residue, p.S1651F, has been reported once by BIC and is classified as uncertain significance by a laboratory in ClinVar. Thus, this variant is currently classified as a "Variant of Uncertain Significance (VUS)," due to lack of sufficient clinical and functional studies at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2015	This variant is denoted BRCA1 c.4951T>C at the cDNA level, p.Ser1651Pro (S1651P) at the protein level, and results in the change of a Serine to a Proline (TCC>CCC). Using alternate nomenclature, this variant would be defined as BRCA1 5070T>C. This variant has been evaluated in a cisplatin response based functional assay but yielded ambivalent results (Bouwman 2013). BRCA1 Ser1651Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1651Pro occurs at a position that is conserved in mammals and is located in the BRCT1 and DNA binding domains as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1651Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2020

The p.S1651P variant (also known as c.4951T>C), located in coding exon 14 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4951. The serine at codon 1651 is replaced by proline, an amino acid with similar properties. This alteration was shown to disrupt the function of the protein in multiple functional studies using different assays (Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Bouwman P et al. Clin Cancer Res, 2020 Sep;26:4559-4568). This alteration was observed in with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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 limited at this time, the clinical significance of this alteration remains unclear. -

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

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.9	.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;N;.;D;.;N;D;D;N;D
REVEL	Pathogenic	0.79
Sift	Benign	0.033	D;D;.;D;.;D;D;D;D;D
Sift4G	Benign	0.19	T;D;D;T;T;D;T;.;.;T
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;D;.
Vest4		0.86
MVP		0.99
MPC		0.39
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254042; hg19: chr17-41222980;