17-43070979-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):c.4935G>C(p.Arg1645Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1645G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3 O:1
• Conservation: PhyloP100: -0.323

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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 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=0.21237522).
• BP6: Variant 17-43070979-C-G is Benign according to our data. Variant chr17-43070979-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55321.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4935G>C	p.Arg1645Ser	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4935G>C	p.Arg1645Ser	missense_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Dec 23, 2003	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2018	This variant is denoted BRCA1 c.4935G>C at the cDNA level, p.Arg1645Ser (R1645S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant, also known as BRCA1 c.5054G>C by alternate nomenclature, has been observed in individuals with breast and/or ovarian cancer (Pal 2005, Haffty 2009, Ruiz 2014, Nakamura 2015). BRCA1 Arg1645Ser was not observed in large population cohorts (Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1645Ser is located in the BRCT1 domain and a region known to interact with multiple other proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Arg1645Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 05, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 27, 2016	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The BRCA1 p.Arg1645Ser variant was identified in 3 of 1332 proband chromosomes (frequency: 0.002) from individuals or families with Ovarian and Breast cancers (Haffty 2009, Pal 2005, Ruiz 2014). The variant was also identified in dbSNP (ID: rs80357373 “With Uncertain significance allele”. This variant was not identified in the Exome Variant Server project and Exome Aggregation Consortium (ExAC-released March 14, 2016) databases. The p.Arg1645Ser variant was identified in the Clinvar database and was classified as variant of uncertain significance by Ambry Genetics, GeneDx and BIC; Invitae did not provide a classification. The BIC database identified the variant 1X with unknown clinical importance. The p.Arg1645 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant amino acid Serine (Ser) is present in African clawed frog, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	12
Dann	Benign	0.93
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.036	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.17	T;D;.;T;.;D;T;T;T;T
Sift4G	Benign	0.077	T;T;T;D;D;T;T;.;.;D
Polyphen		0.36, 0.010	.;B;.;.;.;.;.;.;B;.
Vest4		0.23
MVP		0.58
MPC		0.12
ClinPred		0.13	T
GERP RS		-0.045
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.33

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: rs80357373; hg19: chr17-41222996;