17-43104897-C-G

Variant names:

• chr17-43104897-C-G
• rs1333635543
• NM_007294.4:c.272G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001407959.1(BRCA1):​c.-110G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407959.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.0470

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09103757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.272G>C	p.Cys91Ser	missense_variant	Exon 5 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.272G>C	p.Cys91Ser	missense_variant	Exon 5 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 01, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C91S variant (also known as c.272G>C), located in coding exon 4 of the BRCA1 gene, results from a G to C substitution at nucleotide position 272. The cysteine at codon 91 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is poorly 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

-

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.55
DEOGEN2	Benign	0.086	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.74	T;T;T;T;D;T;D;T;D;D;T;T;T;D;T;T;D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	N;N;N;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.060	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;.
Sift4G	Benign	0.80	T;T;T;T;T;T;.;.;T;.;T;.;T;.;T;.;.;.
Polyphen		0.0010, 0.0050, 0.0	.;B;.;.;.;B;.;.;.;.;B;.;.;.;.;.;.;.
Vest4		0.20
MutPred		0.42		Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);.;Loss of methylation at K88 (P = 0.0601);.;Loss of methylation at K88 (P = 0.0601);.;.;Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);.;Loss of methylation at K88 (P = 0.0601);Loss of methylation at K88 (P = 0.0601);.;.;
MVP		0.52
MPC		0.10
ClinPred		0.016	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1333635543; hg19: chr17-41256914;