17-43092941-A-G

Position:

• chr17-43092941-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_007294.4(BRCA1):​c.2590T>C​(p.Ser864Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S864L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.09

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43092940-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2590T>C	p.Ser864Pro	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2590T>C	p.Ser864Pro	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
MutationTaster	Benign	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.88
MutPred		0.49		Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);.;Loss of MoRF binding (P = 0.053);
MVP		0.94
MPC		0.51
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.66
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41244958;