rs80356983

chr17-43093636-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):c.1895G>A(p.Ser632Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,794 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S632S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 0.0450

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20323801).
• BP6: Variant 17-43093636-C-T is Benign according to our data. Variant chr17-43093636-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1895G>A	p.Ser632Asn	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1895G>A	p.Ser632Asn	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251112 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135728

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461794 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727188

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: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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)	Dec 30, 1999	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Feb 02, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 22, 2023	This missense variant replaces serine with asparagine at codon 632 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast or ovarian cancer (PMID: 32438681) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000173). This variant has been identified in 1/251112 chromosomes 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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2022	This missense variant replaces serine with asparagine at codon 632 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 2 individuals affected with breast or ovarian cancer (PMID: 32438681) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000173). This variant has been identified in 1/251112 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 14, 2022	The p.S632N variant (also known as c.1895G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1895. The serine at codon 632 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been identified in 2/517 individuals diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:). This amino acid position is well 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 06, 2024

Variant summary: BRCA1 c.1895G>A (p.Ser632Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1895G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2071del, p.Arg691fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 54385). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with BRCA1-related cancers (Santonocito et al., 2020); Also known as 2014G>A; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12531920, 15235020, 16518693, 23704879, 10923033, 15343273, 32438681) -

BRCA1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

The BRCA1 c.1895G>A variant is predicted to result in the amino acid substitution p.Ser632Asn. This variant has been reported in two individuals with breast and/or ovarian cancer (Table 2, Santonocito et al. 2020. PubMed ID: 32438681). It has also been reported as clinically significant in an in silico variant interpretation study (Table S3, Tram et al 2013. PubMed ID: 23704879). This variant is reported in 1 of ~251,000 of alleles in gnomAD (http://gnomad.broadinstitute.org/variant/17-41245653-C-T) and has conflicting interpretations of benign and uncertain significance https://preview.ncbi.nlm.nih.gov/clinvar/variation/54385/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D;.;.;.;T;T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.021	D
MutationAssessor	Pathogenic	2.9	M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D;D;D;.;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.025	D;D;D;D;.;D;D
Sift4G	Uncertain	0.048	D;D;D;D;.;D;.
Polyphen		0.93	P;.;.;P;.;.;.
Vest4		0.40
MutPred		0.34		Loss of phosphorylation at S632 (P = 0.0499);Loss of phosphorylation at S632 (P = 0.0499);.;Loss of phosphorylation at S632 (P = 0.0499);.;Loss of phosphorylation at S632 (P = 0.0499);.;
MVP		0.68
MPC		0.16
ClinPred		0.27	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.14

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: rs80356983; hg19: chr17-41245653;