17-43045743-C-G

Variant names:

• chr17-43045743-C-G
• rs80357019
• NM_007294.4:c.5527G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5527G>C​(p.Ala1843Pro) 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 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1843G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 2.75
• Publications: 12 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 70 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43045742-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182082.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 17-43045743-C-G is Pathogenic according to our data. Variant chr17-43045743-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5527G>C	p.Ala1843Pro	missense	Exon 23 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.5593G>C	p.Ala1865Pro	missense	Exon 24 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.5593G>C	p.Ala1865Pro	missense	Exon 24 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5527G>C	p.Ala1843Pro	missense	Exon 23 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5590G>C	p.Ala1864Pro	missense	Exon 24 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5527G>C	p.Ala1843Pro	missense	Exon 23 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 07, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1843P variant (also known as c.5527G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5527. The alanine at codon 1843 is replaced by proline, an amino acid with highly similar properties. This variant was previously detected in a Japanese female with a personal and family history of ovarian cancer (Sekine M et al Clin Cancer Res. 2001; 7(10):3144-50). Functional studies have demonstrated that this variant, which is located in the BRCT domain, results in a moderately destabilizing protein (Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Clapperton JA et al. Nat Struct Mol Biol. 2004; 11(6):512-8; Ambry Internal Data). This variant was previously reported in the SNPDatabase as rs80357019, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this variant is predicted to be possibly damaging and deleterious by PolyPhen and SIFT, as well as other various in silico tools (Mirkovic N et al. Cancer Res., 2004 Jun;64:3790-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Hereditary breast ovarian cancer syndrome Pathogenic:1

Aug 13, 2018

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.5527G>C (p.Ala1843Pro) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246124 control chromosomes (gnomAD). c.5527G>C has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Sekine_2001). This data does not allow any conclusion about variant significance. Several functional studies have found the variant to be moderately destabilizing in multiple measures such as reduced protein stability, significantly decreased transcriptional activity, and homologous recombination (Lee_2010, Rowling_2010, Gaboriau_2015). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.98
MPC		0.50
ClinPred		0.97	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80357019; hg19: chr17-41197760;