17-43095861-C-G

Position:

• chr17-43095861-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007294.4(BRCA1):​c.655G>C​(p.Asp219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.185

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.655G>C	p.Asp219His	missense_variant	9/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.655G>C	p.Asp219His	missense_variant	9/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461448 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2023	Observed in individuals with a personal or family history of breast, ovarian, or other cancers (Li et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 774G>C; This variant is associated with the following publications: (PMID: 9788437, 20215511, 32377563, 29884841, 31853058) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The p.D219H variant (also known as c.655G>C), located in coding exon 8 of the BRCA1 gene, results from a G to C substitution at nucleotide position 655. The aspartic acid at codon 219 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234087). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 219 of the BRCA1 protein (p.Asp219His). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.084	.;T;.;.;.;.;T;.;.;T;.;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	1.2	L;L;L;L;.;L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;.;T;T;T;.;T;.
Polyphen		0.85, 0.91, 0.0020	.;P;.;.;.;P;.;.;B;.;.;.;.
Vest4		0.22
MutPred		0.19		Loss of phosphorylation at S220 (P = 0.1469);Loss of phosphorylation at S220 (P = 0.1469);Loss of phosphorylation at S220 (P = 0.1469);Loss of phosphorylation at S220 (P = 0.1469);.;Loss of phosphorylation at S220 (P = 0.1469);.;.;Loss of phosphorylation at S220 (P = 0.1469);Loss of phosphorylation at S220 (P = 0.1469);.;Loss of phosphorylation at S220 (P = 0.1469);.;
MVP		0.78
MPC		0.29
ClinPred		0.17	T
GERP RS		-1.4
Varity_R		0.032
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs273902779; hg19: chr17-41247878;