rs80357033

chr17-43106467-A-Cchr17-43106467-A-Gchr17-43106467-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_007294.4(BRCA1):c.201T>G(p.Asp67Glu) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D67Y) has been classified as Benign.

• 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: 0.262

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 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18480179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.201T>G	p.Asp67Glu	missense_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.201T>G	p.Asp67Glu	missense_variant	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 27, 2002	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 14, 2016

Variant summary: The BRCA1 c.201T>G (p.Asp67Glu) variant involves the alteration of a non-conserved nucleotide and results in a replacement of an Aspartic acid (D) with a Glutamic acid (E). Both of the residues are medium size and acidic, therefore, this Asp to Glu substitution likely does not alter the physico-chemical properties of the BRCA1 protein. Consistently, 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 118118 control chromosomes while it was reported in three HBOC patients; two of whom had family history of the disease. The variant is located in the central RING domain of BRCA1, in the vicinity of Zn2+ binding site II. Based on a BRCA1 RING model, the Asp67 residue is on the surface of the RING domain and has a side chain with extended orientations favorable for interaction with other proteins. It has been suggested that mutations of this residues would probe the BRCA1 zinc ring domain functionality as a mediator of protein-protein interactions (Bienstock_CanRes_1996). However, experimental studies found that the D67E variant retains the ligase, metal binding and HDR activity of the BRCA1, does not impact BARD1 and UbcH5a binding, barely perturbs BRCA1s native global structure, and only slightly reduced its thermal stability. It has also been shown to slightly inhibit estrogen receptor signaling pathway. The functional studies indicate the variant to be in the neutral spectrum, however, the possibility of an unknown mechanism by which the variant increases the risk of HBOC cannot be excluded, and therefore, it was classified as a variant of uncertain significance until more information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	12
Dann	Benign	0.60
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.3	L;L;L;L;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.79	D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.37	N;N;N;N;N;N;N;N;N;.;N;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;.;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T;T;.;T;T;.;T;T;.;.
Polyphen		0.65, 0.24, 0.0	.;P;.;.;.;B;.;.;B;.;.;.;.;.
Vest4		0.60
MutPred		0.73		Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;
MVP		0.83
MPC		0.082
ClinPred		0.033	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.21

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: rs80357033; hg19: chr17-41258484; COSMIC: COSV104621479; COSMIC: COSV104621479;