17-43104900-A-G

Position:

• chr17-43104900-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007294.4(BRCA1):​c.269T>C​(p.Ile90Thr) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I90F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 O:1
• Conservation: PhyloP100: 3.82

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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.269T>C	p.Ile90Thr	missense_variant	5/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.269T>C	p.Ile90Thr	missense_variant	5/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, single submitter

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Apr 06, 1999	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 19, 2016

Variant summary: The BRCA1 c.269T>C (p.Ile90Thr) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Isoleucine (I) with a medium size and polar Threonine (T). Residues 8-22 and 81-96 of BRCA1 protein form antiparallel alpha-helices flanking the central RING domain (residues 23-76), and are thought to be critical for the proper association of the BRCA1 and BARD1 proteins (Brzovic_Nat Struct Biol_2001). Consistently, 4/5 in silico tools predict the variant to be deleterious. 4/5 in silico tools predict a damaging outcome. This variant is absent in 121322 control chromosomes. It was reported once by the BIC database in one individual from an HBOC family however, without strong evidence for pathogenicity. Functional studies demonstrated the variant to be proficient in BARD1 and UbcH5a binding and to slightly decrease E3 activity of BRCA1. Most importantly, the variant was shown not to have a significant impact on homology directed repair activity of BRCA1 which is essential for its tumor suppressing function. The functional studies indicate the variant to be in the neutral spectrum, however, due to lack of stronger clinical information about variant carries, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T;T;T;T;D;T;D;T;T;D;T;T;T;D;T;T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.1	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.20	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D;T;T;T;T;T;T;T;T;T;D;.;D;T;D;D;D;.
Sift4G	Benign	0.14	T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.;.;.
Polyphen		0.96, 0.98, 1.0	.;P;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Vest4		0.51
MutPred		0.48		Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);.;Loss of stability (P = 0.0278);.;Loss of stability (P = 0.0278);.;.;Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);.;Loss of stability (P = 0.0278);Loss of stability (P = 0.0278);.;.;
MVP		1.0
MPC		0.45
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs80357174; hg19: chr17-41256917;