17-43074381-G-C

Position:

• chr17-43074381-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.4625C>G​(p.Ser1542Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 0.947

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_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2329722).
• BP6: Variant 17-43074381-G-C is Benign according to our data. Variant chr17-43074381-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55242.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.4625C>G	p.Ser1542Cys	missense_variant	14/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.4625C>G	p.Ser1542Cys	missense_variant	14/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251360 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727210

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: 0.0000324

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2021	Variant summary: BRCA1 c.4625C>G (p.Ser1542Cys) results in a non-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 allele was found at a frequency of 0.00011 in 251472 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00011 vs 0.001), allowing no conclusion about variant significance. c.4625C>G has been reported in the literature in individuals affected with breast and ovarian cancers (Akilzhanova_2013, Arver_2001, Koul_2000, Lu_2012, Mucaki_2016, Shih_2000, Tanner_2000). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies showed the variant to have proficient transcriptional activation (Woods_2016, Fernandes_2019) while another showed the variant to deregulate BRCA1-mediated double stranded break repair via ATM phosphorylation (Tram_2013). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2017	- -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Feb 02, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 19, 2016	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2018	This variant is associated with the following publications: (PMID: 10550055, 23704879, 11240689, 11106241, 22476429, 21338495, 10815905, 11156530, 16721040, 10918303, 26898890, 11336395, 25348012, 28781887, 30765603) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2020	The BRCA1 c.4625C>G; p.Ser1542Cys variant (rs41293457) is reported in the literature in individuals with breast cancer (Lu 2012, Shih 2000), and is reported in the ClinVar database (Variation ID: 55242). This variant is found in the general population with an overall allele frequency of 0.004% (9/251360 alleles) in the Genome Aggregation Database. The serine at codon 1542 is moderately conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. S1542 is phosphorylated by ATM and may be involved in response to DNA double-strand breaks (Cortez 1999). However, functional characterization of the variant suggests this variant is likely not pathogenic (Woods 2016). Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Cortez D et al. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science. 1999 Nov 5;286(5442):1162-6. Lu W et al. Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer. 2012 Sep;11(3):381-5. Shih HA et al. BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers. Clin Cancer Res. 2000 Nov;6(11):4259-64. Woods NT et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2016;1. pii: 16001. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.13	.;T;.;.;T;.;.;.;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;N;.;N;.;N;N;N;D;N
REVEL	Uncertain	0.42
Sift	Benign	0.075	T;T;.;T;.;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;.;.;T
Polyphen		0.98, 0.025	.;D;.;.;.;.;.;.;B;.
Vest4		0.21
MVP		0.73
MPC		0.17
ClinPred		0.024	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.039
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41293457; hg19: chr17-41226398;