17-43104914-C-G

Variant names:

• chr17-43104914-C-G
• rs756499058
• NM_007294.4:c.255G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.255G>C​(p.Glu85Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E85V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.655
• Publications: 11 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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 89 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.255G>C	p.Glu85Asp	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.255G>C	p.Glu85Asp	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jul 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;D;T;T;D;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.66
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.58	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.52	T;D;D;T;D;T;D;T;T;D;D;.;D;D;D;T;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;.;.;T;.;D;.;D;.;D;.;.;.
Polyphen		0.98, 0.99, 0.97	.;D;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Vest4		0.39
MutPred		0.29		Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);.;Loss of methylation at K88 (P = 0.0853);.;Loss of methylation at K88 (P = 0.0853);.;.;Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);.;Loss of methylation at K88 (P = 0.0853);Loss of methylation at K88 (P = 0.0853);.;.;
MVP		0.90
MPC		0.32
ClinPred		0.70	D
GERP RS		1.1
PromoterAI		-0.0025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs756499058; hg19: chr17-41256931;