chr17-43092935-G-T

Variant names:

• chr17-43092935-G-T
• rs41286300
• NM_007294.4:c.2596C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.2596C>A​(p.Arg866Ser) 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. R866H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42
• Publications: 1 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2596C>A	p.Arg866Ser	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2596C>A	p.Arg866Ser	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.13	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.79
MutPred		0.68		Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);.;Loss of MoRF binding (P = 0.0185);
MVP		0.92
MPC		0.48
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.81
gMVP		0.59

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

Other links and lift over

dbSNP: rs41286300; hg19: chr17-41244952;