17-43090945-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_007294.4(BRCA1):c.4184A>G(p.Gln1395Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,456,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1395H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 4.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43090944-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232793.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4184A>G	p.Gln1395Arg	missense_variant, splice_region_variant	11/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4184A>G	p.Gln1395Arg	missense_variant, splice_region_variant	11/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456328 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723824

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant replaces glutamine with arginine at codon 1395 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional assays have reported that this variant does not impact transcription activation (PMID: 30765603, 32377563) and disrupted PALB2 binding in a mammalian two-hybrid assay (PMID: 28781887). The reference Gln1395 along with Thr1394 for a TQ motif that may be important for ATM/ATR recognition during DNA damage response and cell cycle checkpoint (PMID: 34301763). This variant has been reported in an individual affected with breast cancer (PMID: 19491284) and multifactorial analysese have reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic covariant, family history and personal and family history of cancer of 1.1391, 0.0272 and 0.958, respectively (PMID: 31131967, 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 10, 2012	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 11, 2022

Variant summary: BRCA1 c.4184A>G (p.Gln1395Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant alters a conserved nucleotide located in the exonic-splice region close to the the adjacent intronic splice donor site, 4/4 computational tools predict no significant impact on normal splicing. Although a slight weakening of the canonical 5' splicing donor site is predicted, to our knowledge, these observations have not been confirmed by published functional studies. This variant is also known as 4303A>G (legacy name). The variant was absent in 242736 control chromosomes (gnomAD). c.4184A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer without evidence for causality (example, Haffty_2009, Judkins_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Two publications report experimental evidence evaluating an impact on protein function. Woods_2016, assessed the transcriptional activation in the presence of the variant, which was found to be about 70% of wild type activity. Then, authors assessed transcriptional activation in the presence of a PALB2 fusion protein and also found the variant to decrease transcriptional activation. More recently, Foo_2021, demonstrated that this variant causes reduced homologous recombination (HR)mediated repair of DNA double-strand breaks (DSB), increased single-strand annealing (SSA), and reduced cellular resistance to DNA damaging agents. The authors concluded that this variant has functional defects and may potentially increase cancer risk or affect prognosis. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=2) and likely benign (n=1). Some submitters cite overlapping, but not identical evidence utilized in the context of this evaluation. Based on the emerging functional evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 15, 2020

Observed in at least one patient with early onset breast cancer (Haffty 2009); Published functional studies demonstrate no damaging effect: transcriptional activation similar to wild type (Woods 2016); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 4303A>G; This variant is associated with the following publications: (PMID: 16267036, 19491284, 21523855, 23704879, 28781887) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The p.Q1395R variant (also known as c.4184A>G), located in coding exon 10 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4184. The glutamine at codon 1395 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in an a cohort of African American women with early-onset breast cancer (Haffty BG Ann. Oncol. 2009 Oct; 20:1653-9). This alteration was called a variant of uncertain significance by VarCall, a Bayesian hierarchical model estimating the likelihood of pathogenicity given functional data (Woods NT et al. NPJ Genom. Med. 2016 Mar;1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;T;D;T;.;.;T;.
Polyphen		0.011, 1.0, 0.82	.;B;.;.;.;D;.;P;.;.
Vest4		0.66
MutPred		0.23		.;Gain of MoRF binding (P = 0.0451);Gain of MoRF binding (P = 0.0451);.;.;.;.;.;.;.;
MVP		0.98
MPC		0.47
ClinPred		0.89	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.37
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356972; hg19: chr17-41242962;